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Cancer Medicine Sep 2019Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies,... (Meta-Analysis)
Meta-Analysis
The incidence of infusion reactions associated with monoclonal antibody drugs targeting the epidermal growth factor receptor in metastatic colorectal cancer patients: A systematic literature review and meta-analysis of patient and study characteristics.
BACKGROUND
Systemic cancer therapies may induce infusion reactions (IRs) or hypersensitivities. Metastatic colorectal cancer (mCRC) patients treated with anti-EGFR therapies, including cetuximab and panitumumab, may be subject to these reactions. We conducted a meta-analysis to estimate the IR incidence in this population and identify variations in this incidence by patient or study characteristics.
METHODS
A systematic review was conducted to identify observational studies or clinical trials of mCRC patients treated with anti-EGFR therapies that reported occurrences of IRs, hypersensitivity, or allergy/anaphylaxis. The objective of the study was to estimate the incidence of IRs. Random effects models were used to meta-analyze the incidence of IRs overall and stratified by therapy type, study design, geographic location, RAS or KRAS mutation status, grade of reaction severity, and terminology used to describe the reaction.
RESULTS
The pooled estimate for IR incidence was 4.9% (95% confidence interval: 3.6%-6.5%). Lower-grade reactions were more common than higher-grade reactions overall and the incidence of reactions among cetuximab patients was nearly four times that of panitumumab patients (6.1% vs 1.6%).
CONCLUSIONS
IRs occur in approximately 5% of mCRC patients treated with anti-EGFR therapies, and the incidence varies significantly by grade of severity and therapy type. Studies evaluating these outcomes should consider investigating survival outcomes by IR status to determine its prognostic relevance.
Topics: Antibodies, Monoclonal; Cetuximab; Colorectal Neoplasms; Drug Hypersensitivity; ErbB Receptors; Humans; Incidence; Infusions, Intravenous; Observational Studies as Topic; Panitumumab; United States
PubMed: 31376243
DOI: 10.1002/cam4.2413 -
Medicine International 2024The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing...
The present systematic review evaluated the effectiveness of anti-EGFR therapy in combination with radiotherapy (RT) or with chemoradiation compared with the existing standard of care for the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). The PubMed, SCOPUS, EMBASE and COCHRANE databases were searched and 12 phase III randomized controlled trials were included. The effectiveness of the anti-EGFR monoclonal antibody cetuximab was evaluated in nine trials. Nimotuzumab (one trial), zalutumumab (one trial) and panitumumab (one trial) were the monoclonal antibodies evaluated in the remaining three trials. One study tested the effectiveness of adding cetuximab to radical RT and found that patients with LAHNSCC exhibited improvement in locoregional control (LRC), overall survival (OS) and progression-free survival (PFS) compared with those of patients treated with RT alone. A total of three studies tested the effectiveness of adding an anti-EGFR agent to chemoradiation. Of these, a single institution study in which patients received cisplatin at 30 mg/m weekly, instead of the standard doses of 100 mg/m every 3 weeks or 40 mg/m every week, reported significant improvement in PFS with the addition of nimotuzumab to chemoradiotherapy without an improvement in overall survival. However, the other two studies indicated that, when added to standard chemoradiation, the anti-EGFR monoclonal antibodies cetuximab or zalutumumab did not improve survival outcomes. Two phase III trials evaluated RT plus an anti-EGFR agent compared with chemoradiation alone. Of these, one study reported inferior outcomes with cetuximab-RT in terms of OS and LRC, whereas the other study with panitumumab plus RT failed to prove the non-inferiority. Two trials evaluated induction chemotherapy followed by cetuximab-RT compared with chemoradiotherapy and reported no benefits in terms of OS or PFS. Furthermore, one study evaluated induction chemotherapy followed by cetuximab-RT compared with induction chemotherapy followed by chemoradiotherapy and found no improvement in OS or PFS. Finally, three phase III trials tested the effectiveness of cetuximab plus RT in the treatment of human papillomavirus-positive oropharyngeal carcinoma, and found it to be inferior compared with cisplatin-RT in terms of OS, PFS and failure-free survival. Based on the aforementioned findings, it is difficult to conclude that anti-EGFR therapy in any form has an advantage over conventional chemoradiation in the treatment of LAHNSCC.
PubMed: 38873325
DOI: 10.3892/mi.2024.165 -
PloS One 2015The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC.
OBJECTIVE
To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC.
DATA SOURCES
MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts.
STUDY SELECTION
Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations.
DATA EXTRACTION AND SYNTHESIS
Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity.
RESULTS
EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002).
CONCLUSION AND RELEVANCE
The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Molecular Targeted Therapy; Mutation; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Rate; Treatment Outcome
PubMed: 26275292
DOI: 10.1371/journal.pone.0135599 -
BMC Medicine Nov 2014Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are... (Meta-Analysis)
Meta-Analysis
Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis.
BACKGROUND
Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are potentially life-threatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs.
METHODS
The databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies.
RESULTS
A total of 14,066 patients from 26 randomized controlled trials (RCTs) were included. The use of anti-EGFR-MoAbs significantly increased the risk of developing severe infections (RR 1.34, 95%CI: 1.10 to 1.62, P=0.003) in cancer patients, but not for fatal infections (RR 1.62, 95%CI: 0.81 to 3.26, P=0.18). Meta-regression indicated the infections might possibly occur early in the treatment with anti-EGFR MoAbs. On sub-group analysis, the risk of severe infections significantly varied with tumor type (P=0.001). When stratified by specific anti-EGFR MoAbs, a significantly increased risk of infections with cetuximab was observed (P<0.001), but not for panitumumab (P=0.98). Additionally, the use of anti-EGFR MoAbs significantly increased the risk of severe infections when used in conjunction with cisplatin (RR 1.48, 95%CI 1.22 to 1.79, P<0.001) or irinotecan (RR 1.53, 95%CI 1.12 to 2.10, P=0.008). When stratified by specific infectious events, anti-EGFR-MoAbs significantly increased the risk of developing severe sepsis (RR 4.30, 95%CI: 1.80 to 10.27; P=0.001).
CONCLUSIONS
Anti-EGFR MoAbs treatment significantly increases the risk of developing severe infectious events in cancer patients. The risk may vary with tumor types. Clinicians should be aware of the risks of severe infections with the administration of these drugs in cancer patients.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; ErbB Receptors; Humans; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Sepsis
PubMed: 25369798
DOI: 10.1186/s12916-014-0203-5 -
Clinical Colorectal Cancer Jun 2018Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC)...
Monoclonal antibody inhibitors of the epidermal growth factor receptor (EGFR) have been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC) without RAS gene mutations. However, treatment with anti-EGFR agents can be associated with toxicities of the skin, nails, hair, and eyes. Because these dermatologic toxicities can result in treatment discontinuation and affect patient quality of life, their management is an important focus when administering anti-EGFR monoclonal antibodies. The present systematic review describes the current data reporting the nature and incidence of, and management and treatment options for, dermatologic toxicities occurring during anti-EGFR treatment of mCRC. A search of the National Library of Medicine PubMed database from January 1, 2009, to August 18, 2016, identified relevant reports discussing dermatologic toxicity management among patients with mCRC receiving anti-EGFR therapy. The studies were grouped by type and rated by level of evidence using the GRADE approach developed by the Agency for Healthcare Research and Quality. Overall, 269 reports were reviewed (nonrandomized trials, n = 120; randomized trials, n = 31; retrospective studies, n = 15; reviews, n = 39). Dermatologic toxicity of any grade occurs in most patients who receive anti-EGFR therapy; approximately 10% to 20% of patients experienced grade 3/4 toxicity. The most common dermatologic toxicities include papulopustular/acneiform rash, xerosis, and pruritus; however, nail changes, hair abnormalities, and ocular conditions also occur. Guidance for managing these toxicities includes the use of inexpensive emollient ointments and moisturizers, avoidance of sun exposure, avoidance of irritants, and the use of short showers. Several studies also found that preemptive treatment was more effective than reactive treatment at limiting the incidence and severity of skin toxicity. With appropriate treatment, the dermatologic toxicities associated with anti-EGFR monoclonal antibody therapy can be managed, minimizing patient discomfort and the need for therapy interruption and/or discontinuation. Additionally, preemptive treatment can reduce dermatologic toxicity severity, ultimately yielding better quality of life.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cetuximab; Colorectal Neoplasms; Drug Eruptions; ErbB Receptors; Humans; Incidence; Panitumumab
PubMed: 29576427
DOI: 10.1016/j.clcc.2017.12.004 -
Journal of Managed Care & Specialty... Feb 2019Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been...
BACKGROUND
Pharmacogenetic testing can provide predictive insights about the efficacy and safety of drugs used in cancer treatment. Although many drug-gene associations have been reported in the literature, the strength of evidence supporting each association can vary significantly. Even among the subgroup of drugs classified by the PharmGKB database to have a high or moderate level of evidence, there is limited information regarding the economic value of pharmacogenetic testing.
OBJECTIVES
To: (a) summarize the available pharmacoeconomic evidence assessing the value of pharmacogenetic testing for cancer drugs with clinically relevant drug-gene associations; (b) determine the quality of the studies that contain this evidence; and (c) discuss the quality of this evidence with respect to the level of evidence of the drug-gene associations.
METHODS
The PharmGKB database was used to identify cancer drugs with clinically relevant drug-gene associations graded high (1A, 1B) or moderate (2A, 2B). A systematic literature review was conducted using these drugs. Ovid MEDLINE and Embase databases were searched to identify cost-effectiveness, cost-utility, or cost-minimization studies comparing pharmacogenetic testing to an alternative. Cost and effect values from every relevant comparison within the studies were extracted, and the incremental cost-effectiveness ratio (ICER) was either extracted or calculated for each comparison. Quality assessment was conducted for each study using the Quality of Health Economic Studies (QHES) instrument. Qualitative synthesis was used to summarize the data.
RESULTS
The search yielded 2,191 citations, of which 35 studies met the inclusion criteria. Pharmacoeconomic studies were available for the following drugs from the PharmGKB database: fluoropyrimidine, 6-mercaptopurine, irinotecan, carboplatin, cisplatin, erlotinib, gefitinib, cetuximab, panitumumab, and trastuzumab. The studies were conducted in Asia, Europe, Canada, the United States, and Mexico and reported cost-utility, cost-effectiveness, and cost-minimization outcomes. The mean QHES score was 80 (SD = 22) for the studies of drug-gene pairs with high (1A, 1B) and moderate (2A, 2B) levels of evidence (1A = 82, 1B = 93, 2A = 71, and 2B = 74). There was variation across studies in terms of reporting. 109 relevant comparisons were identified within the studies. Of those that reported cost per life-year or cost per quality-adjusted life-year (n = 58 comparisons), pharmacogenetic testing was dominant in 21% overall and 42%, 21%, 17%, and 5% of the comparisons in Asia, Europe, Canada, and the United States, respectively. Variability was observed in the ICER values regardless of geographic region or drug. Pharmacogenetic testing was cost saving in 17 of 19 cost-minimization comparisons and was favored most frequently when compared with genetically indiscriminate strategies containing the drug of interest.
CONCLUSIONS
There was mixed evidence regarding the value of pharmacogenetic testing to guide cancer treatment. For future pharmacogenomic-related economic studies, we recommend prioritizing clinically relevant drug-gene associations and greater adherence to available best practice guidelines for conducting and reporting economic evaluation studies.
DISCLOSURES
No outside funding supported this review. Part of Hussain's research time was supported by a Merit Review Award (I01 BX000545), Medical Research Service, U.S. Department of Veterans Affairs. Hussain also reports personal fees from Bristol-Myers Squibb, AstraZeneca, Novartis, Bayer HealthCare Pharmaceuticals, and France Foundation, outside the submitted work. Onukwugha reports grants from Pfizer and Bayer HealthCare Pharmaceuticals, along with advisory board fees from Novo Nordisk, outside the submitted work. Faruque, Neuberger, and Noh have nothing to disclose.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Economics, Pharmaceutical; Humans; Neoplasms; Pharmacogenomic Testing; Quality-Adjusted Life Years
PubMed: 30698084
DOI: 10.18553/jmcp.2019.25.2.260 -
Frontiers in Pharmacology 2020Patients with locally advanced rectal cancer (LARC) are at higher risk of local and distant recurrence and are thus more vulnerable to metastatic diseases. Neoadjuvant...
BACKGROUND
Patients with locally advanced rectal cancer (LARC) are at higher risk of local and distant recurrence and are thus more vulnerable to metastatic diseases. Neoadjuvant chemoradiotherapy (nCRT) and subsequent curative resection with total mesorectal excision (TME) followed by adjuvant chemotherapy have been recommended by the National Comprehensive Cancer Network (NCCN) guidelines as standard of care for LARC patients. However, the efficacy of the addition of epidermal growth factor receptor (EGFR) inhibitors in kirsten rat sarcoma viral oncogene (KRAS)-wild type LARC patients remains uncertain.
MATERIALS
PubMed, Embase, and Web of Science were searched to retrieve records on the application of EGFR inhibitors in a neoadjuvant setting for LARC patients. pCR was used as surrogate endpoint to perform data synthesis in a single-arm setting.
RESULTS
Ten cohorts covering 540 subjects were eligible in this systematic review. The pooled pCR rate for EGFR inhibitors was 15% (95% confidence interval (95% CI), 11-20%; I = 55.2%); the pooled estimates of Grade 3/4 diarrhea, Grade 3/4 hand-foot syndrome, Grade 3/4 acneiform rash were 17% (95% CI, 4-34%; I = 93.3%), 2% (95% CI, 0-5%; I = 13.7%), and 15% (95% CI, 9-22%; I = 65.4%), respectively.
CONCLUSION
The addition of EGFR inhibitors in the nCRT for KRAS-wild type LARC patients provides comparable efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by more future studies.
PubMed: 32499700
DOI: 10.3389/fphar.2020.00706