A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial

Johnsson, Anna; Hagman, Helga; Frödin, Jan Erik; Berglund, Åke; Keldsen, Nina; Fernebro, Eva; Sundberg, Jan; Christensen, René De Pont; Spindler, Karen Lise Garm; Bergström, Dan; Jakobsen, Anders

doi:10.1093/annonc/mdt236

Cited by 66 publications

(45 citation statements)

References 15 publications

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“…The NORDIC ACT trial had a similar design, randomly selecting patients to receive maintenance treatment with bevacizumab with or without erlotinib after induction treatment with chemotherapy (CAPIRI, CAPOX, FOLFIRI, OR FOLFOX). 50 The primary endpoint progression-free survival was not signifıcantly different between the two arms, 5.7 compared with 4.2 months, respectively (HR 0.79, p ϭ 0.12). Also median overall survival was comparable in both arms (HR 0.88, p ϭ 0.51).…”

Section: Optimal Duration Of Targeted Therapymentioning

confidence: 86%

Systemic Treatment: Maintenance Compared with Holiday

Punt

Simkens

Koopman

2015

American Society of Clinical Oncology Educational Book

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OVERVIEWWith the currently available cytotoxic and targeted drugs, metastatic colorectal cancer (mCRC) may be controlled by systemic treatment for a substantial period of time. However, many questions remain about the optimal use of drugs and duration of treatment. The feasibility of chemotherapy-free intervals has been studied in patients with mCRC treated with chemotherapy alone, but the results are conflicting. Current data show that oxaliplatin may be safely interrupted, but they do not allow a firm conclusion on the safety of a full treatment break of chemotherapy. For targeted therapy, continuous inhibition of intracellular signaling by prolonged administration would theoretically be beneficial for efficacy of treatment. Recent data support the use of maintenance treatment with chemotherapy and bevacizumab. No data on the optimal duration of treatment with anti-epidermal growth factor receptor (EGFR) agents are currently available. C olorectal cancer is the second most common cause of cancer deaths worldwide, and its incidence is still increasing. Approximately 50% of the patients will eventually develop distant metastases, which may be treated with surgical resection and/or systemic treatment. The systemic treatment for mCRC has changed substantially over the past 20 years. Currently available drugs with proven effıcacy can be classifıed as cytotoxic (i.e., classic chemotherapy) and targeted drugs (e.g., antibodies, small molecules). A large number of patients respond well to treatment, and many patients often ask for drug holidays. If this would not compromise survival, a drug holiday could increase quality of life (QoL) and would reduce health care costs. This paper will review the data on the optimal duration of treatment. 1 CHEMOTHERAPYEffective cytotoxic drugs in mCRC include the fluoropyrimidines, irinotecan, and oxaliplatin. These drugs are the backbone of systemic treatment of mCRC. There is no outright preference for either oxaliplatin or irinotecan in fırst-line combination schedules. 2 Retrospective studies have shown that the exposure to these three cytotoxics during the course of disease appears more important than their up-front combined use. [3][4][5] This has been confırmed by the results of subsequent prospective studies, of which the results showed no benefıt for up-front combination treatment over sequential treatment starting with fluoropyrimidine monotherapy. 6,7 The choice between combination or sequential therapy may depend on several factors, such as tumor-related symptoms, potential resectability of metastases, and performance status. 8 As a result of the improved outcome of treatment, an increasing number of patients continue to do well on chemotherapy. Objective responses are usually achieved within the fırst 4 to 6 months of treatment.

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Section: Optimal Duration Of Targeted Therapymentioning

confidence: 86%

Systemic Treatment: Maintenance Compared with Holiday

Punt

Simkens

Koopman

2015

American Society of Clinical Oncology Educational Book

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“…[10][11][12]14,15,[17][18][19] Of these, 5 trials were selected for additional analysis, because these trials evaluated a separately defined "maintenance phase," with randomization after the induction phase ( . The selected studies were assessed for potential bias with regard to the randomization approach, timely parallel enrollment, similarity of treatment groups, data-driven reporting, analysis population (intent-to-treat [ITT] vs. other), and other aspects.…”

Section: Definition Of Analysis and Trial Selectionmentioning

confidence: 99%

“…The OPTIMOX 3/DREAM and Nordic ACT trials evaluated the addition of erlotinib to bevacizumab maintenance. 10,19 However, erlotinib has not been licensed for mCRC treatment, and approval, considering the data obtained, seems unlikely.…”

Section: Definition Of Analysis and Trial Selectionmentioning

confidence: 99%

“…10,19 Therefore, the licensing and consecutive administration of erlotinib in mCRC maintenance seems unlikely.…”

Section: Alexander Stein Et Almentioning

confidence: 99%

“…[7][8][9] Recent trials allocated patients after 3 to 6 months of induction treatment to different maintenance strategies and/or observation alone. [10][11][12][13][14][15][16] These trials all showed an effect on progression-free survival (PFS) or the respective alternate endpoints eg, time to failure of strategy or time to second progression; however, the effect on OS has remained unclear. The current meta-analysis was performed to compare observation alone with bevacizumab or bevacizumab and chemotherapy maintenance after induction chemotherapy in terms of PFS and OS.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Application and Intensity of Bevacizumab-based Maintenance After Induction Chemotherapy With Bevacizumab for Metastatic Colorectal Cancer: A Meta-analysis

Stein

Schwenke²,

Folprecht

et al. 2016

Clinical Colorectal Cancer

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The role of bevacizumab-based maintenance after first-line bevacizumab-based induction treatment of metastatic colorectal cancer was evaluated in a meta-analysis of 3 randomized trials. Maintenance treatment with bevacizumab with or without fluoropyrimidines improved progression-free survival and showed a trend toward improved overall survival. Background: The administration and intensity of bevacizumab-based maintenance therapy after induction treatment with bevacizumab is still a matter of debate. Thus, the present meta-analysis and an indirect comparison were performed to clarify these issues. Patients and Methods: Trials evaluating a separately defined "maintenance phase," with randomization after the induction phase, were selected. Three trials of maintenance with bevacizumab with or without a fluoropyrimidine (CAIRO3, SAKK 41/06, and AIO KRK 0207) were analyzed regarding the effect on progression-free survival (PFS) and overall survival (OS) of any maintenance therapy compared with observation alone and different maintenance intensities (bevacizumab with or without fluoropyrimidine) compared with observation alone and between each other. Results: Maintenance with bevacizumab with or without fluoropyrimidine after bevacizumabbased induction treatment for 4 to 6 months significantly improved PFS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.43-0.75; P ¼ .0004) and showed a trend toward prolonged OS (HR, 0.89; 95% CI, 0.78-1.02; P ¼ .09) compared with observation alone. The effect on PFS increased with the intensity of the maintenance regimen (HR, 0.72; 95% CI, 0.60-0.85 for single-agent bevacizumab vs. HR, 0.45; 95%, CI 0.39-0.51 for combination therapy, both compared to observation alone). In contrast, the HRs for OS remained in the same range. A similarly improved PFS (HR, 0.63; 95% CI, 0.50-0.79) was shown for the more intensive maintenance therapy (bevacizumab and fluoropyrimidine) compared with bevacizumab alone. Conclusion: Bevacizumab-based maintenance therapy after induction chemotherapy with bevacizumab significantly improves PFS and showed a trend toward prolonged OS and should thus be considered, in particular, in patients with a response to induction treatment.

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Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer

Chan

Segelov

Wong

et al. 2017

Cochrane Database of Systematic Reviews

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The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.

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A randomized phase III trial on maintenance treatment with bevacizumab alone or in combination with erlotinib after chemotherapy and bevacizumab in metastatic colorectal cancer: the Nordic ACT Trial

Abstract: NCT00598156.

Cited by 66 publications

References 15 publications

Systemic Treatment: Maintenance Compared with Holiday

Systemic Treatment: Maintenance Compared with Holiday

Effect of Application and Intensity of Bevacizumab-based Maintenance After Induction Chemotherapy With Bevacizumab for Metastatic Colorectal Cancer: A Meta-analysis

Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer

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