FOLFIRI versus irinotecan monodrug as second-line treatment in metastatic colorectal cancer patients: An open, multicenter, prospective, randomized controlled phase III clinical study.

4038 Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m2; Lecovorin 400mg/m2; 5-Fu 400mg/m2; 5-Fu 2400mg/m2 CIV 46h. Irinotecan monodrug group 180mg/m2, The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .

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Phase III randomized trial comparing systemic versus intra-arterial oxaliplatin, combined with LV5FU2 +/- irinotecan and a targeted therapy, in the first-line treatment of metastatic colorectal cancer restricted to the liver (OSCAR): PRODIGE 49

Digestive and Liver Disease ◽

10.1016/j.dld.2021.12.012 ◽

2022 ◽

Author(s):

Simon Pernot ◽

Olivier Pellerin ◽

Laurent Mineur ◽

Carole Monterymard ◽

Denis Smith ◽

...

Keyword(s):

Colorectal Cancer ◽

Targeted Therapy ◽

Metastatic Colorectal Cancer ◽

Randomized Trial ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.5.1501 ◽

2001 ◽

Vol 19 (5) ◽

pp. 1501-1518 ◽

Cited By ~ 205

Author(s):

Udo Vanhoefer ◽

Andreas Harstrick ◽

Wolf Achterrath ◽

Shousong Cao ◽

Siegfried Seeber ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Topoisomerase I ◽

Clinical Status ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Phase Iii Trials ◽

Line Chemotherapy

PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.

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Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3503 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3503-3503 ◽

Cited By ~ 11

Author(s):

Dieter Koeberle ◽

Daniel C. Betticher ◽

Roger Von Moos ◽

Daniel Dietrich ◽

Peter Brauchli ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Statistical Power ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Open Label ◽

Line Chemotherapy ◽

First Line Treatment

3503 Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after stop of first-line chemotherapy. Methods: In an open-label, phase 3 multicenter study conducted in Switzerland, patients with unresectable metastatic colorectal cancer having non-progressive disease after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned in a 1:1 ratio to continuing bevacizumab (7.5 mg/kg every 3 weeks) or no treatment. CT scans were done every 6 weeks between randomization and disease progression. The primary endpoint was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significant level of 10% and a statistical power of 85%. Results: The per-protocol population comprised 262 patients. Median follow-up is 28.6 months (range, 0.6-54.9 months). Median TTP was 17.9 weeks (95% CI 13.3-23.4) for bevacizumab continuation and 12.6 weeks (95% CI 12.0-16.4) for no continuation; HR 0.72 (95% CI 0.56-0.92). Median progression free-survival and overall survival, both measured from start of first-line treatment, was 9.5 months and 24.9 months for bevacizumab continuation and 8.5 months (HR 0.73 (95% CI 0.57 - 0.94)) and 22.8 months (HR 0.87 (95% CI 0.64 – 1.18)) for no continuation. Median time from randomization to second-line treatment was 5.9 months for bevacizumab and 4.8 for no continuation. Grade 3-4 adverse events in the bevacizumab continuation arm were uncommon. Conclusions: Non-inferiority could not be demonstrated. The 95% confidence intervals for the TTP HR indicate superiority of bevacizumab continuation after stop of first-line chemotherapy. The median differences in TTP and in time between randomization and start of second-line treatment were of moderate magnitude being less than 6 weeks. The results of an accompanying cost analysis will be presented at the meeting. Clinical trial information: NCT00544700.

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Efficacy and Toxicity of Addition of Bevacizumab to Chemotherapy in Patients with Metastatic Colorectal Cancer

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666190119162352 ◽

2019 ◽

Vol 21 (10) ◽

pp. 718-724 ◽

Cited By ~ 2

Author(s):

Wen-Cong Ruan ◽

Yue-Ping Che ◽

Li Ding ◽

Hai-Feng Li

Keyword(s):

Colorectal Cancer ◽

Adverse Event ◽

Metastatic Colorectal Cancer ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Clinical Prognosis ◽

Line Therapy ◽

Significant Difference

Background: Pre-treated patients with first-line treatment can be offered a second treatment with the aim of improving their poor clinical prognosis. The therapy of metastatic colorectal cancer (CRC) patients who did not respond to first-line therapy has limited treatment options. Recently, many studies have paid much attention to the efficacy of bevacizumab as an adjuvant treatment for metastatic colorectal cancer. Objectives: We aimed to evaluate the efficacy and toxicity of bevacizumab plus chemotherapy compared with bevacizumab-naive based chemotherapy as second-line treatment in people with metastatic CRC. Methods: Electronic databases were searched for eligible studies updated to March 2018. Randomized-controlled trials comparing addition of bevacizumab to chemotherapy without bevacizumab in MCRC patients were included, of which, the main interesting results were the efficacy and safety profiles of the addition of bevacizumab in patients with MCRC as second-line therapy. Result: Five trials were eligible in the meta-analysis. Patients who received the combined bevacizumab and chemotherapy treatment in MCRC as second-line therapy showed a longer overall survival (OS) (OR=0.80,95%CI=0.72-0.89, P<0.0001) and progression-free survival (PFS) (OR=0.69,95%CI=0.61-0.77, P<0.00001). In addition, there was no significant difference in objective response rate (ORR) (RR=1.36,95%CI=0.82-2.24, P=0.23) or severe adverse event (SAE) (RR=1.02,95%CI=0.88-1.19, P=0.78) between bevacizumab-based chemotherapy and bevacizumabnaive based chemotherapy. Conclusion: Our results suggest that the addition of bevacizumab to the chemotherapy therapy could be an efficient and safe treatment option for patients with metastatic colorectal cancer as second-line therapy and without increasing the risk of an adverse event.

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Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era

International Journal of Molecular Sciences ◽

10.3390/ijms22147717 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7717

Author(s):

Guido Giordano ◽

Pietro Parcesepe ◽

Giuseppina Bruno ◽

Annamaria Piscazzi ◽

Vincenzo Lizzi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Line Treatment ◽

Second Line ◽

Wild Type ◽

First Line ◽

Braf Mutations ◽

Mutational Status ◽

First Line Treatment

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.

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Randomized phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group

Annals of Oncology ◽

10.1093/annonc/mdx122 ◽

2017 ◽

Vol 28 (6) ◽

pp. 1288-1293 ◽

Cited By ~ 25

Author(s):

J.J.M. Kwakman ◽

L.H.J. Simkens ◽

J.M. van Rooijen ◽

A.J. van de Wouw ◽

A.J. ten Tije ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Phase Iii Trial ◽

Cancer Group ◽

First Line Treatment

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Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil–Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.1.136 ◽

2000 ◽

Vol 18 (1) ◽

pp. 136-136 ◽

Cited By ~ 954

Author(s):

S. Giacchetti ◽

B. Perpoint ◽

R. Zidani ◽

N. Le Bail ◽

R. Faggiuolo ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Objective Response ◽

Sensory Neuropathy ◽

Phase Iii ◽

Line Treatment ◽

Survival Times ◽

First Line ◽

Grade 3 ◽

First Line Treatment

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)–leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m2/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m2, as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU–LV occurred in ≤ 5% of the patients (≤ 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU–LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU–LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU–LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU–LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

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Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group

Clinical Colorectal Cancer ◽

10.1016/j.clcc.2019.01.002 ◽

2019 ◽

Vol 18 (2) ◽

pp. e229-e230

Author(s):

Johannes J.M. Kwakman ◽

Erik van Werkhoven ◽

Lieke H.J. Simkens ◽

Johan M. van Rooijen ◽

Yes A.J. van de Wouw ◽

...

Keyword(s):

Colorectal Cancer ◽

Survival Analysis ◽

Metastatic Colorectal Cancer ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Phase Iii Trial ◽

Cancer Group ◽

First Line Treatment

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Cost-effectiveness analysis of cetuximab combined with chemotherapy as a first-line treatment for patients with RAS wild-type metastatic colorectal cancer based on the TAILOR trial

BMJ Open ◽

10.1136/bmjopen-2019-030738 ◽

2020 ◽

Vol 10 (2) ◽

pp. e030738 ◽

Cited By ~ 1

Author(s):

Huijuan Wang ◽

Lingfei Huang ◽

Peng Gao ◽

Zhengyi Zhu ◽

Weifeng Ye ◽

...

Keyword(s):

Colorectal Cancer ◽

Cost Effectiveness ◽

Metastatic Colorectal Cancer ◽

Survival Benefit ◽

Cost Effective ◽

Phase Iii ◽

Line Treatment ◽

Wild Type ◽

First Line ◽

First Line Treatment

ObjectivesCetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX-4) is superior to FOLFOX-4 alone as a first-line treatment for patients with metastatic colorectal cancer with RAS wild-type (RAS wt mCRC), with significantly improved survival benefit by TAILOR, an open-label, randomised, multicentre, phase III trial. Nevertheless, the cost-effectiveness of these two regimens remains uncertain. The following study aims to determine whether cetuximab combined with FOLFOX-4 is a cost-effective regimen for patients with specific RAS wt mCRC in China.DesignA cost-effectiveness model combined decision tree and Markov model was built to simulate pateints with RAS wt mCRC based on health states of dead, progressive and stable. The health outcomes from the TAILOR trial and utilities from published data were used respectively. Costs were calculated with reference to the Chinese societal perspective. The robustness of the results was evaluated by univariate and probabilistic sensitivity analyses.ParticipantsThe included patients were newly diagnosed Chinese patients with fully RAS wt mCRC.InterventionsFirst-line treatment with either cetuximab plus FOLFOX-4 or FOLFOX-4.Main outcome measuresThe primary outcomes are costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs).ResultsBaseline analysis disclosed that the QALYs was increased by 0.383 caused by additional cetuximab, while an increase of US$62 947 was observed in relation to FOLFOX-4 chemotherapy. The ICER was US$164 044 per QALY, which exceeded the willingness-to-pay threshold of US$28 106 per QALY.ConclusionsDespite the survival benefit, cetuximab combined with FOLFOX-4 is not a cost-effective treatment for the first-line regime of patients with RAS wt mCRC in China.Trial registration numberTAILOR trial (NCT01228734); Post-results.

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