Metastatic Colorectal Cancer Study Critical Review
| INTRODUCTION | |
| Background | Cancer has become one of the major deadly diseases in the world presented in different forms. Colorectal cancer is one of the significant malignancies in the United States, with an estimated 145,600 people diagnosed with colorectal cancer. An estimated 51,020 died of colorectal cancer in 2019.2 Treatment intervention of these conditions has been evolving with a major consideration of specific treatment that can improve the rate of recovery. There is no particular treatment for cancer, although early detection has been associated with a higher rate of improvement.
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| Previous trials | 1. Azad NS, Posadas EM, Kwitkowski VE et al. Combination targeted therapy with Sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 2008 26:3709-3714.3 39 patients were treated with 5mg/kg or 10mg/kg with bevacizumab and sorafenib 200 mg twice daily. Adverse events of hypertension, hand-foot syndrome, diarrhoea, transaminitis and fatigue occurred in patients. A dose reduction of sorafenib to 200mg/day was required to tolerate treatment. The findings from the study defined that a combination of sorafenib and bevacizumab have greater clinical outcomes in patients with ovarian cancer. However, the findings dosage is different, considering that the frequency and rapidity of sorafenib at 200mg twice daily with 5,g/kg every 2 weeks might not be tolerable in the long-term. The researchers highlighted that alternative sorafenib dosage schedules should be considered in future studies.
2. Lee JM, Sarosy GA Annunziata CM et al. Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity. Br J Cancer 2010; 102:495-499.4 17 patients were treated with alternating doses of sorafenib 200 mg twice daily and bevacizumab 5mg/kg, and 10mg/kg. The results also determined that intermittent sorafenib dosing together with bevacizumab has improved clinical activity with lower sorafenib dose reduction and side effects.
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| Why this study? | Treatment of different types of cancer has been a major challenge, especially in relation to the high number of individuals who are being diagnosed with cancer. Colorectal cancer is associated with increased deaths, especially patients who are diagnosed with the condition while at stage IV. Different interventions have been used, although with a lower level of efficacy. There has been an understanding of the effect of bevacizumab in the treatment of colorectal cancer. Sorafenib has the potential to complement the bevacizumab activity through blocking of VEGF signalling in patients with progressive disease of metastasis colorectal cancer.
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| GENERAL STUDY OVERVIEW | |
| Title/Citation | Dual VEGF inhibition with sorafenib and bevacizumab as salvage therapy in metastatic colorectal cancer: results of the phase North Central Cancer Treatment Group study N054C (Alliance).
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| Funding | The study received financial support in the form of a grant from the National Cancer Institute of the National Institutes of Health, the Alliance for Clinical Trials in Oncology. The research was also supported by funds from Beyer and Genentech.
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| Trial design | The study employed the use of case-control experimental research design. |
| Objectives | The purpose of the study was to investigate the activity of combined vertical of VEGF signalling with sorafenib and bevacizumab as rescue therapy among patients having progressive disease on all standard therapy in metastatic colorectal cancer. |
| METHODS | |
| Inclusion criteria | The study participants included: · Patients diagnosed with stage IV colorectal cancer and aged 18 years or older. · Patients who accepted blood samples to be taken. · Patients who consented to participate in the study for the study duration.
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| Exclusion criteria | The study excluded patients : · Patients who had a life expectancy of fewer than six months were excluded from the study. · Patients who were not willing to provide blood samples were also excluded. · The authors excluded patients with known brain metastatic as well as uncontrolled hypertension, high blood pressure, as well as other patients with other uncontrolled medical conditions.
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| Interventions | Measurable disease and progressive within six months after the standard therapy. These are included the use of BEV, fluoropyrimidine, oxaliplation, among others as prescribed. The study also included therapy restrictions among the respondents. These restrictions included patients with no prior sorafenib therapy, no discontinuation of BEV, as well as no current anticoagulant. |
| Outcome measures | Primary outcome The study sought to investigate the total number of respondents who began and finished the intervention based on the time period that was outlined. Secondary outcomes The research also sought to investigate whether a combination of BEV and sorafenib were essential in the treatment of patients with stage IV colorectal cancer.
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| Statistical analyses | The study included a two-stage Simon design was used. The distribution of OS was estimated using Kaplan-Meier methodology. Simple frequency analysis was conducted to determine whether the Response rate was related to prior treatment. Descriptive statistics were used to investigate how prior treatment affected various other measures.
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| RESULTS | |
| Enrollment | A total of 83 participants were included in the study, although only 79 met all the inclusion criteria and were based on in the analysis of the results.
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| Baseline characteristics | The findings from the study showed that the median age of the respondents was 62 years, with the youngest participant being 36 years and the oldest being 88 years. The analysis shows that 54% were males, while 46% were female. KRAS status was also investigated where 49% had wild type while 51% had mutated. The most common metastatic included liver, (80%), Lung (66%) and Nodal (58%).
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| Efficacy | Primary outcome A total of 565 treatment cycles were administered in the study. The median percentage dose was 100% BEV and 85% for sorafenib, 39% ( n= 31) delayed treatment at least once during the time of the study 16%( n = 13) omitted a dose of BEV at least one while 33% (n =26) omitted a dose of sorafenib at least once.
Secondary Outcome The assessment of the outcomes showed that from the 79 participants, 42 of them were progression-free at three months. At the initial tumor assessment, 22 patients were found to have progressed, and six went of treatment before having tumor assessments done. The reasons for treatment discontinuation were PD, adverse events, patient refusal, death, and physician decision. Genetic variant association results presented a higher understanding of the different variables that were included in the study. The univariate analysis that was conducted showed that presence of Mutant T allele in the 5′ UTR of the VEGF was significantly associated with fewer successes in the progression-free rate at the three months follow up ( p = 0.026, p<0.05). The results also showed that after correcting for multiple comparisons showed that there were no differences observed between the genotype subgroups and either progression-free rate at three months or the most common grade ≥3 AE (p >0.05).
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| Adverse events/safety | To control any adverse or safety issues and challenges while carrying out the study, the researcher’s sought approval from the Mayo Clinic Institutional Review Board and the North Central Cancer Treatment Group. Ensuring that the study met all the underlying ethical guidelines improves the quality of results where it is possible to identify significant changes. |
| AUTHORS’ CONCLUSIONS | |
| The findings from the study showed that the use of a combination of BEV a sorafenib as a rescue intervention in heavily pretreated metastatic colorectal cancer patients is more efficient compared to a single response. It was found that the combination is tolerable and manageable, with evidence showing improving results.
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| GENERALIZABILITY/CRITIQUE/DICUSSION | |
| Patient Population | The study included a sample size of 79. Even though it is possible to focus on this sample and make conclusions, it is crucial to identify the need to improve the findings of the study through the integration of a better approach that helps improve change. Including more sample participants would have been effective in making a conclusion regarding the use of a combined intervention of sorafenib and BEV. Obtaining significant results is highly influenced by the underlying level of significance and the sample size. A higher level of relevance increases the degree of error hence reducing the accuracy of the results. A smaller sample size reduces the accuracy of the results since the use of the same intervention of a different population is likely to have a negative influence on the findings.
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| Intervention | The researchers have identified that angiogenesis is a substantial tumor growth, invasion, and metastases. The vascular endothelial growth factor is considered a more pro-angiogenic factor that is a vital mediator of angiogenesis. VEGF-A has been over-expressed mainly in a variety of human cancers, including metastatic colorectal cancer. Therefore, it is crucial to focus on VEGF-A for biologic therapy in controlling metastatic colorectal cancer. The BEV inhibits the VEGF-A interaction with its existing receptors, which include the VEGFR-1 and 2, which in turn neutralize VEGF-A activity. However, the study identifies that the past researches have shown that single-agent treatment with BEV has been associated with little activity in metastatic colorectal cancer. This study aims at assessing a combination of BEV and sorafenib. |
| Endpoints | The study focuses on improving the efficacy of the existing treatment for metastatic cancer through the evaluation assessment of combined therapy. This information has been made clear, forming the basis of the study. The purpose of the research has been well outlined, which presents a more substantial system that defines change and integration of better approaches that help in ensuring that the critical points of the study are known for improved reliability and validity of the findings.
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| Statistics | The trial and control groups have not been effectively identified in the study. It understands the different groups in the study help in ensuring that there is a clear emphasis on research outcomes based on the underlying concepts that promote change. The degree of difference when using the combined intervention has not been fully identified, which provides a different perspective that can be fully assessed and present a highly specific system that can improve the accuracy of the findings. Understanding the influence of each intervention would have helped in understanding the influence of the combined intervention. The methodology has been well outlined with a clear structure where the study findings have been adequately analyzed and presented. The use of experimental research design offers a clear emphasis on efficacy and the ability to understand whether the use of a combined intervention between sorafenib and BEV can help improve the wellbeing of patients with metastatic colorectal cancer. This is an evidence-based practice that helps improve on the existing interventions that can help in controlling adverse outcomes among colorectal cancer. However, based on the inclusion strategy, the study excluded many patients, especially those who were having uncontrolled medical conditions. The reduced sample that the research was working with makes it difficult to determine whether the results would be the same in a more extensive study. |
| Conclusions | The study presents a better understanding of different interventions that can be used on metastatic patients and help improve their health and wellbeing. The authors have outlined that the use of BEV alone has had improved results among the patients who presented an improved focus on sorafenib, which has mainly been successful in treating patients with other types of cancer.
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References:
- Xie,H., Lafky, J. M., Morlan B. Stella, P.J Dakhil, S. R., Gross 2020. Dual VEGF inhibition with sorafenib and bevacizumab as salvage therapy in metastatic colorectal cancer: results of the phase II North Central Cancer Treatment Group study N054C(Alliance). Therapeutic advances in medical oncology 2020 12, 17588359210913.
- Siegel RL, Miller, KD and Jemal A. Cancer statistics, 2019 CA Cancer J CLIN 2019:69;7-34.
- Azad NS, Posadas EM, Kwitkowski VE, et al. Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 2008; 26:3709-3714.
- Lee JM, Sarosy GA Annuunization CM et al. Combination therapy: intermittent sorafenib with bevacizizumab yields activity and decreased toxicity. Br J Cancer 2010; 102 495-499.
- Grothey A and Allegra C. Antiangiogionesis therapy in the treatment of metastatic colorectal cancer. Ther Ad Med Oncol 2012;4;301-319.
- Berghoff, A., & Preusser, M, Anti-angiogenic therapies in brain metastases. Magazine of European Medical Oncology 2018 11(1), 14-17.
- Duonerba C., Di Lorenza G., Sonpavde G., 2016, Combination therapy for metastatic renal cell carcinoma. Annals of translational medicine, 2016 4.(5).
- Clarke, J, Neil E., Terziiew et al. Multicenter, phase 1 dose-escalation study of hypofractionated stereotactic radiation therapy with bevacizumab for recurrent glioblastoma and anaplastic astrocytoma. International Journal of Radiation Oncology Biology Physics 2017, 99 (4) 797-804.
- Hubbard JM, Mahoney MR, Loui WS et al., Phase I/II randomized trial of sorafenib and bevacizumab as first-line therapy in patients with locally advanced or metastatic hepatocellular carcinoma: Northcentral cancer treatment group trial N0745(Alliance) 2017 Targeted oncology 12(2), 201-209.
Supplements
The study was previously presented in part in 2010 and 2011. In the assessment of conflict of interest, mayo Clinic Foundation received funding for research activities which were carried out by Grothey from Genentech and Bayer Oncology. All other authors did not have a conflict of interest.