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Clinical Colorectal Cancer Mar 2016To evaluate, from a US payer perspective, the cost-effectiveness of treatment strategies for metastatic colorectal cancer (mCRC), we performed a systematic review of... (Review)
Review
To evaluate, from a US payer perspective, the cost-effectiveness of treatment strategies for metastatic colorectal cancer (mCRC), we performed a systematic review of published cost-effectiveness analyses. We identified 14 papers that fulfilled our search criteria and revealed varying levels of value among current treatment strategies. Older agents such as 5-fluorouracil, irinotecan, and oxaliplatin provide high-value treatments. More modern agents targeting the EGFR or VEGF pathways, such as bevacizumab, cetuximab, and panitumumab, do not appear to be cost-effective treatments at their current costs. The analytical methods used within the papers varied widely, and this variation likely plays a significant role in the heterogeneity in incremental cost-effectiveness ratios. The cost-effectiveness of current treatment strategies for mCRC is highly variable. Drugs recently approved by the US Food and Drug Administration for mCRC are not cost-effective, and this is primarily driven by high drug costs.
Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Costs; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Quality-Adjusted Life Years; Treatment Outcome; United States
PubMed: 26541320
DOI: 10.1016/j.clcc.2015.10.002 -
Health Technology Assessment... Jun 2017Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit... (Review)
Review
The clinical effectiveness and cost-effectiveness of cetuximab (review of technology appraisal no. 176) and panitumumab (partial review of technology appraisal no. 240) for previously untreated metastatic colorectal cancer: a systematic review and economic evaluation.
BACKGROUND
Colorectal cancer is the fourth most commonly diagnosed cancer in the UK after breast, lung and prostate cancer. People with metastatic disease who are sufficiently fit are usually treated with active chemotherapy as first- or second-line therapy. Targeted agents are available, including the antiepidermal growth factor receptor (EGFR) agents cetuximab (Erbitux, Merck Serono UK Ltd, Feltham, UK) and panitumumab (Vecitibix, Amgen UK Ltd, Cambridge, UK).
OBJECTIVE
To investigate the clinical effectiveness and cost-effectiveness of panitumumab in combination with chemotherapy and cetuximab in combination with chemotherapy for rat sarcoma () wild-type (WT) patients for the first-line treatment of metastatic colorectal cancer.
DATA SOURCES
The assessment included a systematic review of clinical effectiveness and cost-effectiveness studies, a review and critique of manufacturer submissions, and a de novo cohort-based economic analysis. For the assessment of effectiveness, a literature search was conducted up to 27 April 2015 in a range of electronic databases, including MEDLINE, EMBASE and The Cochrane Library.
REVIEW METHODS
Studies were included if they were randomised controlled trials (RCTs) or systematic reviews of RCTs of cetuximab or panitumumab in participants with previously untreated metastatic colorectal cancer with WT status. All steps in the review were performed by one reviewer and checked independently by a second. Narrative synthesis and network meta-analyses (NMAs) were conducted for outcomes of interest. An economic model was developed focusing on first-line treatment and using a 30-year time horizon to capture costs and benefits. Costs and benefits were discounted at 3.5% per annum. Scenario analyses and probabilistic and univariate deterministic sensitivity analyses were performed.
RESULTS
The searches identified 2811 titles and abstracts, of which five clinical trials were included. Additional data from these trials were provided by the manufacturers. No data were available for panitumumab plus irinotecan-based chemotherapy (folinic acid + 5-fluorouracil + irinotecan) (FOLFIRI) in previously untreated patients. Studies reported results for WT subgroups. First-line treatment with anti-EGFR therapies in combination with chemotherapy appeared to have statistically significant benefits for patients who are WT. For the independent economic evaluation, the base-case incremental cost-effectiveness ratio (ICER) for WT patients for cetuximab plus oxaliplatin-based chemotherapy (folinic acid + 5-fluorouracil + oxaliplatin) (FOLFOX) compared with FOLFOX was £104,205 per quality-adjusted life-year (QALY) gained; for panitumumab plus FOLFOX compared with FOLFOX was £204,103 per QALY gained; and for cetuximab plus FOLFIRI compared with FOLFIRI was £122,554 per QALY gained. The ICERs were sensitive to treatment duration, progression-free survival, overall survival (resected patients only) and resection rates.
LIMITATIONS
The trials included WT populations only as subgroups. No evidence was available for panitumumab plus FOLFIRI. Two networks were used for the NMA and model, based on the different chemotherapies (FOLFOX and FOLFIRI), as insufficient evidence was available to the assessment group to connect these networks.
CONCLUSIONS
Although cetuximab and panitumumab in combination with chemotherapy appear to be clinically beneficial for WT patients compared with chemotherapy alone, they are likely to represent poor value for money when judged by cost-effectiveness criteria currently used in the UK. It would be useful to conduct a RCT in patients with WT.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42015016111.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Humans; Male; Neoplasm Metastasis; Panitumumab; Technology Assessment, Biomedical; Treatment Outcome
PubMed: 28682222
DOI: 10.3310/hta21380 -
Critical Reviews in Oncology/hematology Nov 2023In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR... (Review)
Review
BACKGROUND
In RAS wild type (wt) metastatic colorectal cancer (mCRC) maintenance therapy after induction with fluoropyrimidine (FP)-based cytotoxic therapy (CT) plus anti-EGFR agents is controversial.
METHODS
Phase II-III randomized trials were included. Maintenance strategies considered were: observation, anti-EGFR or FP monotherapy, FP + anti-EGFR, doublet CT + anti-EGFR.
RESULTS
Maintenance with FP + anti-EGFR (HR 0.56, 95% CrI 0.36-0.89) showed the greatest PFS benefit compared to observation, ranking first on SUCRA analysis (96.4%). Considering OS, doublet CT+ anti-EGFR, FP + anti-EGFR and anti-EGFR monotherapy yielded similar results. For PFS, FP + anti-EGFR confirmed to be valuable in BRAF wt patients and left sided tumors. In left sided tumors, the OS benefit of adding CT was limited. FP plus anti-EGFR showed a favourable safety profile compared to doublet CT + anti-EGFR.
CONCLUSIONS
FP + anti-EGFR can be considered a valuable maintenance option in RAS wt mCRC. EGFR monotherapy can be considered, especially in left-sided tumors.
PubMed: 37659764
DOI: 10.1016/j.critrevonc.2023.104106 -
The Oncologist Oct 2023HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR... (Meta-Analysis)
Meta-Analysis
BACKGROUND
HER2 overexpression/amplification in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) may be associated with resistance to standard-of-care anti-EGFR therapies. Given the lack of comprehensive investigations into this association, we assessed the prognostic or predictive effect of HER2 amplification/overexpression on anti-EGFR treatment outcomes.
METHODS
A systematic review of MEDLINE, Embase, and Cochrane Library (2001-2021) identified studies evaluating progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) in HER2-positive vs. HER2-negative patients with RAS WT mCRC who received anti-EGFR treatments and whose HER2 status was known. Meta-analyses of proportions (ORR) and hazard ratios (PFS, OS) were performed using random-effect models with pre-specified sensitivity analyses.
RESULTS
Five high-quality retrospective cohort studies were included in the meta-analyses representing 594 patients with mCRC. All patients received anti-EGFR treatment, either as monotherapy or in combination with chemotherapy. Meta-analysis of PFS demonstrated a 2.84-fold higher risk of death or progression (95% CI, 1.44-5.60) in patients with HER2-positive (vs. HER2-negative) RAS WT mCRC treated with anti-EGFR regimens. The odds of response to anti-EGFR treatment were 2-fold higher in HER2-negative vs. HER2-positive (odds ratio, 1.96 [95% CI, 1.10-3.48]). Differences in OS were not statistically significant. Sensitivity analyses confirmed the robustness of the base-case estimates.
CONCLUSIONS
While this study could not account for all confounding factors, in patients with RAS WT mCRC who received anti-EGFR therapy, HER2 overexpression/amplification was associated with worse PFS and ORR and may therefore predict poorer outcomes. HER2 testing is important to inform treatment decisions and could optimize outcomes for patients.
Topics: Humans; Antibodies, Monoclonal; Colorectal Neoplasms; Retrospective Studies; ErbB Receptors; Panitumumab; Colonic Neoplasms; Rectal Neoplasms; Proto-Oncogene Proteins p21(ras); Antineoplastic Combined Chemotherapy Protocols
PubMed: 37463037
DOI: 10.1093/oncolo/oyad200 -
International Journal of Cancer Nov 2016Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with... (Meta-Analysis)
Meta-Analysis Review
Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).
Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; ErbB Receptors; Humans; Neoplasms; Panitumumab; Randomized Controlled Trials as Topic; Thromboembolism
PubMed: 27450994
DOI: 10.1002/ijc.30280 -
Critical Reviews in Oncology/hematology Sep 2020The most effective regimen is unclear for patients with recurrent or metastatic head and neck squamous cell carcinomas (R/M HNSCC). We performed a systematic review and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The most effective regimen is unclear for patients with recurrent or metastatic head and neck squamous cell carcinomas (R/M HNSCC). We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating only systemic therapy for R/M HNSCC.
METHODS
This systematic review followed PRISMA and the Cochrane Collaboration Handbook for Systematic Reviews of Interventions. Endpoints included overall survival (OS), progression-free survival (PFS) and overall response rates (ORR).
RESULTS
55 RCTs from 1990-November 2019 qualified for review (n=12132). Only PD-1/PDL-1 inhibitors increased OS in R/M HNSCC platinum-resistant disease against their control (HR = 0·79, 95%CI 0·70-0.90, p<0·001), especially for PD-L1 ≥ 1% expressing tumours (HR = 0·72, 95%CI 0·60-0·86, p<0·001). PFS was prolonged for anti-EGFR agents against methotrexate when used in a second line setting (HR = 0·74, 95 %CI 0·62-0·87, p=0·001), and when cetuximab (HR = 0·60, 95%CI 0·49-0·72, p<0·0001) and panitumumab (HR = 0·76, 95%CI 0·65-0·89, p=0·001) were introduced to platinum-based regimens for first-line treatment.
CONCLUSIONS
PD-1/PD-L1 inhibitors may represent the future of R/M HNSCC treatment. However, EGFR inhibitors may still play improve clinical outcomes.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Head and Neck Neoplasms; Humans; Methotrexate; Neoplasm Recurrence, Local; Squamous Cell Carcinoma of Head and Neck
PubMed: 32569853
DOI: 10.1016/j.critrevonc.2020.102984 -
Scientific Reports Feb 2018Hypomagnesemia is a recognized side-effect of cetuximab- or panitumumab-based chemotherapy for metastatic colorectal cancer (mCRC). The clinical relevance of... (Meta-Analysis)
Meta-Analysis Review
Hypomagnesemia is a recognized side-effect of cetuximab- or panitumumab-based chemotherapy for metastatic colorectal cancer (mCRC). The clinical relevance of hypomagnesemia is under debate. Thus, a systematic review and meta-analysis of retrospective studies and randomized clinical trials (RCTs) comparing hypomagnesemia with normal magnesium levels in wild-type KRAS mCRC was performed. One RCT, two retrospective studies, and two American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) conference presentations from phase III RCTs involving 1723 patients were included in this study. Patients with hypomagnesemia demonstrated better progression-free survival (PFS) (Hazard ratio [HR]: 0.64; 95% confidence interval [CI]: 0.47-0.88), overall survival (OS) (HR: 0.72; 95% CI: 0.53-0.92), and objective response rate (ORR) (Risk ratio [RR]: 1.81; 95% confidence interval [CI]: 1.30-2.52). By subgroup analysis, frontline, later lines or combination therapy with hypomagnesemia were associated with PFS benefits (HR: 0.78; 95% CI: 0.62-0.98; HR: 0.60; 95% CI: 0.40-0.90; HR: 0.62; 95% CI: 0.41-0.94, respectively). In patients with wild-type KRAS mCRC, hypomagnesemia is associated with better clinical benefits of PFS, OS and ORR when treated with cetuximab- or panitumumab-based chemotherapy. Future clinical trials should corroborate its predictive role.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Humans; Magnesium; Neoplasm Metastasis; Panitumumab; Proto-Oncogene Proteins p21(ras); Randomized Controlled Trials as Topic; Survival Analysis
PubMed: 29391418
DOI: 10.1038/s41598-018-19835-8 -
Ecancermedicalscience 2015The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited... (Review)
Review
BACKGROUND
The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients.
OBJECTIVE
To assess the effectiveness and safety of MA in the treatment of MCRC.
METHODS
A systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC.
RESULTS
Sixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10-2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08-1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes.
CONCLUSION
The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS.
PubMed: 26557880
DOI: 10.3332/ecancer.2015.582 -
Annals of Oncology : Official Journal... Jan 2015Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) prolong survival in metastatic colorectal cancer (mCRC) Kirsten rat sarcoma viral oncogene (KRAS) exon 2 wild-type tumors. Recent evidence has suggested that other RAS mutations (in exons 3 and 4 of KRAS and exons 2, 3 and 4 of a related gene, NRAS) may also be predictive of resistance.
METHODS
Systematic review and meta-analysis of randomized, controlled trials (RCTs) evaluating anti-EGFR mAbs that have assessed tumors for new RAS mutations. Tumors with the new RAS mutations were compared with both tumors without any RAS mutations and tumors with KRAS exon 2 mutations with respect to anti-EGFR treatment progression-free survival (PFS) and overall survival (OS) benefit.
RESULTS
Nine RCTs comprising a total of 5948 participants evaluated for both KRAS exon 2 and new RAS mutations met the inclusion criteria. Approximately 20% of KRAS exon 2 wild-type tumors harbored one of the new RAS mutations. Tumors without any RAS mutations (either KRAS exon 2 or new RAS mutations) were found to have significantly superior anti-EGFR mAb PFS (P < 0.001) and OS (P = 0.008) treatment effect compared with tumors with any of the new RAS mutations. No difference in PFS or OS benefit was evident between tumors with KRAS exon 2 mutations and tumors with the new RAS mutations. Results were consistent between different anti-EGFR agents, lines of therapy and chemotherapy partners. Anti-EGFR mAb therapy significantly improved both PFS {hazard ratio 0.62 [95% confidence interval (CI) 0.50-0.76]} and OS [hazard ratio 0.87 (95% CI 0.77-0.99)] for tumors without any RAS mutations. No PFS or OS benefit was evident with use of anti-EGFR mAbs for tumors harboring any RAS mutation (P > 0.05).
CONCLUSION
Tumors harboring one of the new RAS mutations are unlikely to significantly benefit from anti-EGFR mAb therapy in mCRC.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Drug Resistance, Neoplasm; ErbB Receptors; GTP Phosphohydrolases; Humans; Membrane Proteins; Panitumumab; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins
PubMed: 25115304
DOI: 10.1093/annonc/mdu378 -
Frontiers in Oncology 2021Systemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This...
BACKGROUND
Systemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This study aimed to provide the complete efficacy and safety profiles and ranking of systemic therapies for the treatment of unresectable advanced or metastatic CRC.
METHODS
We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until June 30, 2021, and also the bibliographies of relevant studies. Randomized controlled trials comparing two or more treatments, namely, at least capecitabine, 5-fluorouracil, leucovorin, irinotecan, bevacizumab, cetuximab, oxaliplatin, or panitumumab were investigated. A network meta-analysis using the Bayesian approach was performed to compare the efficacy and safety of treatments. The surface under the cumulative ranking curve (SUCRA) was calculated for the probability of each treatment as the most effective. The overall response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) grade ≥3, and serious adverse events (SAEs) were evaluated.
RESULTS
One hundred two publications with 36,147 participants were assigned to 39 different treatments. Among 11 treatments with full information on six outcomes, FOLFIRI/FOLFOX/FOLFOXIRI + bevacizumab significantly improved both the ORR and DCR, compared to FOLFIRI. Although FOLFOX and FOLFIRI/FOLFOX + cetuximab significantly prolonged both OS and PFS, treatments were comparable in terms of AEs grade ≥3 and SAEs. The top highest SUCRA values were observed in the FOLFOXIRI + panitumumab group for ORR (96%) and DCR (99%), FOLFIRI + bevacizumab + panitumumab group for OS (62%) and PFS (54%), and FOLFOXIRI + bevacizumab group for AEs grade ≥3 (59%) and SAEs (59%) outcomes.
CONCLUSIONS
These findings suggest an available range of systemic treatment therapies with different efficacy and safety profiles with patients. Further investigations of the side effects and mutation status are required to confirm our findings.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/, identifier CRD42019127772.
PubMed: 35223449
DOI: 10.3389/fonc.2021.756214