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Abstract
The use of data from the real world to address clinical and policy-relevant questions that cannot be answered using data from clinical trials is garnering increased interest. Indeed, data from cancer registries and linked treatment records can provide unique insights into patients, treatments and outcomes in routine oncology practice. In this Review, we explore the quality of real-world data (RWD), provide a framework for the use of RWD and draw attention to the methodological pitfalls inherent to using RWD in studies of comparative effectiveness. Randomized controlled trials and RWD remain complementary forms of medical evidence; studies using RWD should not be used as substitutes for clinical trials. The comparison of outcomes between nonrandomized groups of patients who have received different treatments in routine practice remains problematic. Accordingly, comparative effectiveness studies need to be designed and interpreted very carefully. With due diligence, RWD can be used to identify and close gaps in health care, offering the potential for short-term improvement in health-care systems by enabling them to achieve the achievable.
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Neugut AI, Lin A, Raab GT, Hillyer GC, Keller D, O'Neil DS, Accordino MK, Kiran RP, Wright J, Hershman DL. FOLFOX and FOLFIRI Use in Stage IV Colon Cancer: Analysis of SEER-Medicare Data. Clin Colorectal Cancer 2019; 18:133-140. [PMID: 30878317 DOI: 10.1016/j.clcc.2019.01.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/23/2019] [Accepted: 01/25/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Shortly after the year 2000, randomized trials demonstrated that patients with metastatic colon cancer treated with infusional 5-fluorouracil (5-FU)/leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) had a comparable progression-free survival benefit, superior to patients who received 5-FU/leucovorin alone. Factors associated with the initial receipt of the FOLFOX or FOLFIRI regimen are unknown. Our goal was to investigate the patterns and predictors of use for first-line FOLFOX and FOLFIRI. PATIENTS AND METHODS We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data set to identify patients with newly diagnosed stage IV colon cancer between the years 2005 and 2013 who received either first-line FOLFOX or FOLFIRI. We used logistic regression to assess demographic and clinical predictors for FOLFOX versus FOLFIRI. Survival was compared by Kaplan-Meier models. RESULTS Overall, 3000 patients (79.3%) received FOLFOX and 785 (20.7%) FOLFIRI. FOLFOX was associated with later year of diagnosis (odds ratio [OR] = 0.66, 95% confidence interval [CI], 0.54 to 0.82 for 2011-2013 vs. 2005-2007), being female (OR = 0.82; 95% CI 0.69 to 0.98), and living in the southern region of the United States. FOLFIRI was associated with having a higher comorbidity index (OR = 1.33; 95% CI, 1.07 to 1.67 for >1 comorbidity score vs. 0). There was no survival difference observed between the two treatments. CONCLUSION The majority of SEER-Medicare patients received FOLFOX and not FOLFIRI as a first-line treatment for stage IV colon cancer. Several demographic and clinical factors were associated with the use of each specific regimen. No survival difference was detected for the 2 groups.
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Affiliation(s)
- Alfred I Neugut
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY.
| | - Aijing Lin
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Gabriel T Raab
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Grace Clarke Hillyer
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Deborah Keller
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Daniel S O'Neil
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Melissa Kate Accordino
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Ravi P Kiran
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY
| | - Jason Wright
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Obstetrics and Gynecology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
| | - Dawn L Hershman
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
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Bradley CJ, Yabroff KR, Warren JL, Zeruto C, Chawla N, Lamont EB. Trends in the Treatment of Metastatic Colon and Rectal Cancer in Elderly Patients. Med Care 2016; 54:490-7. [DOI: 10.1097/mlr.0000000000000510] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Lester-Coll NH, Rutter CE, Bledsoe TJ, Goldberg SB, Decker RH, Yu JB. Cost-Effectiveness of Surgery, Stereotactic Body Radiation Therapy, and Systemic Therapy for Pulmonary Oligometastases. Int J Radiat Oncol Biol Phys 2016; 95:663-72. [PMID: 27055395 DOI: 10.1016/j.ijrobp.2016.01.020] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 01/06/2016] [Accepted: 01/12/2016] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Pulmonary oligometastases have conventionally been managed with surgery and/or systemic therapy. However, given concerns about the high cost of systemic therapy and improvements in local treatment of metastatic cancer, the optimal cost-effective management of these patients is unclear. Therefore, we sought to assess the cost-effectiveness of initial management strategies for pulmonary oligometastases. METHODS AND MATERIALS A cost-effectiveness analysis using a Markov modeling approach was used to compare average cumulative costs, quality adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) among 3 initial disease management strategies: video-assisted thoracic surgery (VATS) wedge resection, stereotactic body radiation therapy (SBRT), and systemic therapy among 5 different cohorts of patient disease: (1) melanoma; (2) non-small cell lung cancer adenocarcinoma without an EGFR mutation (NSCLC AC); (3) NSCLC with an EGFR mutation (NSCLC EGFRm AC); (4) NSCLC squamous cell carcinoma (NSCLC SCC); and (5) colon cancer. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to analyze uncertainty with regard to model parameters. RESULTS In the base case, SBRT was cost effective for melanoma, with costs/net QALYs of $467,787/0.85. In patients with NSCLC, the most cost-effective strategies were SBRT for AC ($156,725/0.80), paclitaxel/carboplatin for SCC ($123,799/0.48), and erlotinib for EGFRm AC ($147,091/1.90). Stereotactic body radiation therapy was marginally cost-effective for EGFRm AC compared to erlotinib with an incremental cost-effectiveness ratio of $126,303/QALY. For colon cancer, VATS wedge resection ($147,730/2.14) was the most cost-effective strategy. Variables with the greatest influence in the model were erlotinib-associated progression-free survival (EGFRm AC), toxicity (EGFRm AC), cost of SBRT (NSCLC SCC), and patient utilities (all histologies). CONCLUSIONS Video-assisted thoracic surgery wedge resection or SBRT can be cost-effective in select patients with pulmonary oligometastases, depending on histology, efficacy, and tolerability of treatment and patient preferences.
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Affiliation(s)
- Nataniel H Lester-Coll
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut.
| | - Charles E Rutter
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
| | - Trevor J Bledsoe
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
| | - Sarah B Goldberg
- Department of Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Roy H Decker
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
| | - James B Yu
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut
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Yajima S, Shimizu H, Sakamaki H, Ikeda S, Ikegami N, Murayama JI. Real-world cost analysis of chemotherapy for colorectal cancer in Japan: detailed costs of various regimens during the entire course of chemotherapy. BMC Health Serv Res 2016; 16:2. [PMID: 26728154 PMCID: PMC4698819 DOI: 10.1186/s12913-015-1253-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Accepted: 12/24/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Various chemotherapy regimens for advanced colorectal cancer have been introduced to clinical practice in Japan over the past decade. The cost profiles of these regimens, however, remain unclear in Japan. To explore the detailed costs of different regimens used to treat advanced colorectal cancer during the entire course of chemotherapy in patients treated in a practical setting, we conducted a so-called "real-world" cost analysis. METHOD A detailed cost analysis was performed retrospectively. Patients with advanced colorectal cancer who had received chemotherapy in a practical healthcare setting from July 2004 through October 2010 were extracted from the ordering system database of Showa University Hospital. Direct medical costs of chemotherapy regimens were calculated from the hospital billing data of the patients. The analysis was conducted from a payer's perspective. RESULTS A total of 30 patients with advanced colorectal cancer were identified. Twenty patients received up to second-line treatment, and 8 received up to third-line treatment. The regimens identified from among all courses of treatment in all patients were 13 oxaliplatin-based regimens, 31 irinotecan-based regimens, and 11 regimens including molecular targeted agents. The average (95% confidence interval [95% CI]) monthly cost during the overall period from the beginning of treatment to the end of treatment was 308,363 (258,792 to 357,933) Japanese yen (JPY). According to the type of regimen, the average monthly cost was 418,463 (357,413 to 479,513) JPY for oxaliplatin-based regimens, 215,499 (188,359 to 242,639) JPY for irinotecan-based regimens, and 705,460 (586,733 to 824,187) JPY for regimens including molecular targeted agents. Anticancer drug costs and hospital fees accounted for 50 to 77% and 11 to 25% of the overall costs of chemotherapy, respectively. CONCLUSION The costs of irinotecan-based regimens were lower than those of oxaliplatin-based regimens and regimens including molecular targeted agents in Japan. Using a lower cost regimen for first-line treatment can potentially reduce the overall cost of chemotherapy. The main cost drivers were the anticancer drug costs and hospitalization costs.
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Affiliation(s)
- Shuichi Yajima
- Department of Health Policy and Management, School of Medicine, Keio University, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. .,Taiho Pharmaceutical Co., Ltd., 1-27, Kandanishiki-cho, Chiyoda-ku, Tokyo, 101-8444, Japan.
| | - Hisanori Shimizu
- Department of Pharmacy Services, Showa University Hospital, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Hiroyuki Sakamaki
- School of Management, Tokyo University of Science, 500, Shimokiyoku, Kuki, Saitama, 346-8512, Japan
| | - Shunya Ikeda
- Department of Pharmaceutical Sciences, School of Pharmacy, International University of Health and Welfare, 2600-1 Kitakanemaru, Otawara, Tochigi, 324-8501, Japan
| | - Naoki Ikegami
- Keio University, 5-29-20-409 Shiba, Minato-ku, Tokyo, 108-0014, Japan
| | - Jun-Ichiro Murayama
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
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Sampson VB, Vetter NS, Kamara DF, Collier AB, Gresh RC, Kolb EA. Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways. PLoS One 2015; 10:e0142704. [PMID: 26571493 PMCID: PMC4646493 DOI: 10.1371/journal.pone.0142704] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 10/26/2015] [Indexed: 11/03/2022] Open
Abstract
Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.
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Affiliation(s)
- Valerie B. Sampson
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America
| | - Nancy S. Vetter
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America
| | - Davida F. Kamara
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America
| | - Anderson B. Collier
- Department of Pediatrics, Division of Hematology and Oncology, Children's Healthcare of Mississippi, University of Mississippi Medical Center, Jackson, MS, United States of America
| | - Renee C. Gresh
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America
| | - E. Anders Kolb
- Nemours Center for Cancer and Blood Disorders, Nemours/A.I. duPont Hospital for Children, Wilmington, Delaware, United States of America
- * E-mail:
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Marschner N, Arnold D, Engel E, Hutzschenreuter U, Rauh J, Freier W, Hartmann H, Frank M, Jänicke M. Oxaliplatin-based first-line chemotherapy is associated with improved overall survival compared to first-line treatment with irinotecan-based chemotherapy in patients with metastatic colorectal cancer - Results from a prospective cohort study. Clin Epidemiol 2015; 7:295-303. [PMID: 25945067 PMCID: PMC4408959 DOI: 10.2147/clep.s73857] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE Several randomized trials investigating the preferable first-line combination chemotherapy regimen for metastatic colorectal cancer have shown inconsistent findings. Because a substantial number of patients are still being treated with "chemo-only" first-line therapies without targeted agents, we compared overall survival (OS) of patients treated in routine practice with oxaliplatin-fluoropyrimidine and irinotecan-fluoropyrimidine. PATIENTS AND METHODS Using the database of the Tumor Registry Colorectal Cancer, we identified 605 patients with metastatic colorectal cancer who received first-line fluoropyrimidine combination chemotherapy with either oxaliplatin (n=430) or irinotecan (n=175). The Tumor Registry Colorectal Cancer is a cohort study that prospectively documents treatment of colorectal cancer by office-based medical oncologists in Germany and has recruited over 5,000 patients. OS was estimated using the Kaplan-Meier method, and a multivariate Cox proportional hazard model was used to adjust for potentially confounding variables. RESULTS Median OS was 26.8 (95% confidence interval [CI] 22.4-31.9) months with an oxaliplatin-fluoropyrimidine combination and 18.3 (95% CI 15.1-23.2) months with irinotecan-fluoropyrimidine first-line "chemo-only" therapy. Median progression-free survival was 9.0 (8.1-10.2) and 7.9 (7.2-10.2) months, respectively. The difference in OS was confirmed if analysis was restricted to patients with synchronous metastases (no prior treatment). Among other variables, proportion of patients receiving any second-line therapy did not differ between groups. Oxaliplatin-based first-line therapy was associated with improved OS in multivariate analysis adjusted for potentially confounding variables (hazard ratio 0.678, 95% CI 0.510-0.901, P=0.007). CONCLUSION In clinical routine practice, first-line treatment with oxaliplatin-fluoropyrimidine combination chemotherapy compared to irinotecan-fluoropyrimidine combination is associated with improved survival in patients with metastatic colorectal cancer, independent of all examined potentially confounding factors.
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Affiliation(s)
- Norbert Marschner
- Praxis für Interdisziplinäre Onkologie und Hämatologie, Freiburg, Germany
| | | | - Erik Engel
- Hämatologisch – Onkologische Praxis Altona, Hamburg, Germany
| | | | - Jacqueline Rauh
- Fachinternistische Gemeinschaftspraxis und Therapiezentrum, Witten, Germany
| | | | - Holger Hartmann
- Clinical Epidemiology and Health Economics, iOMEDICO, Freiburg, Germany
| | | | - Martina Jänicke
- Clinical Epidemiology and Health Economics, iOMEDICO, Freiburg, Germany
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Romanus D, Cardarella S, Cutler D, Landrum MB, Lindeman NI, Gazelle GS. Cost-effectiveness of multiplexed predictive biomarker screening in non-small-cell lung cancer. J Thorac Oncol 2015; 10:586-94. [PMID: 25590606 PMCID: PMC4395466 DOI: 10.1097/jto.0000000000000474] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Population-wide screening for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements to inform cancer therapy in non-small-cell lung cancer (NSCLC) is recommended by guidelines. We estimated cost-effectiveness of multiplexed predictive biomarker screening in metastatic NSCLC from a societal perspective in the United States. METHODS We constructed a microsimulation model to compare the life expectancy and costs of multiplexed testing and molecularly guided therapy versus treatment with cisplatin-pemetrexed (CisPem). All testing interventions included a two-step algorithm of concurrent EGFR mutation and ALK overexpression testing with immunohistochemistry followed by ALK rearrangement confirmation with a fluorescence in situ hybridization assay for immunohistochemistry-positive results. Three strategies were included: "Test-treat" approach, where molecularly guided therapy was initiated after obtainment of test results; "Empiric switch therapy," with concurrent initiation of CisPem and testing and immediate switch to test-result conditional treatment after one cycle of CisPem; and "Empiric therapy" approach in which CisPem was continued for four cycles before start of a tyrosine kinase inhibitor. RESULTS The incremental cost-effectiveness ratio for "Test-treat" compared with treatment with CisPem was $136,000 per quality-adjusted life year gained. Both empiric treatment approaches had less favorable incremental cost-effectiveness ratios. "Test-treat" and "Empiric switch therapy" yielded higher expected outcomes in terms of quality-adjusted life years and life-years than "Empiric therapy." These results were robust across plausible ranges of model inputs. CONCLUSION From a societal perspective, our cost-effectiveness results support the value of multiplexed genetic screening and molecularly guided therapy in metastatic NSCLC.
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Affiliation(s)
- Dorothy Romanus
- *Institute for Technology Assessment, Massachusetts General Hospital, Harvard University, Boston, Massachusetts; †Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; ‡Department of Economics, Harvard University, Cambridge, Massachusetts; §Department of Health Care Policy, Harvard Medical School, Boston, Massachusetts; ‖Department of Pathology, Brigham and Women' Hospital, Harvard Medical School, Boston, Massachusetts; and ¶Institute for Technology Assessment, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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Lairson DR, Parikh RC, Cormier JN, Chan W, Du XL. Cost-utility analysis of chemotherapy regimens in elderly patients with stage III colon cancer. PHARMACOECONOMICS 2014; 32:1005-1013. [PMID: 24920195 DOI: 10.1007/s40273-014-0180-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
BACKGROUND Chemotherapy prolongs survival for stage III colon cancer patients but community-level evidence on the effectiveness and cost effectiveness of treatment for elderly patients is limited. Comparisons were between patients receiving no chemotherapy, 5-fluorouracil (5-FU), and FOLFOX (5-FU + oxaliplatin). METHODS A retrospective cohort study was conducted using the Surveillance Epidemiology, and End Results (SEER)-Medicare linked database. Patients (≥65 years) with American Joint Committee on Cancer stage III colon cancer at diagnosis in 2004-2009 were identified. The 3-way propensity score matched sample included 3,534 patients. Effectiveness was measured in life-years and quality-adjusted life-years (QALYs). Medicare costs (2010 US dollars) were estimated from diagnosis until death or end of study. RESULTS FOLFOX patients experienced 6.06 median life-years and 4.73 QALYs. Patients on 5-FU had 5.75 median life-years and 4.50 median QALYs, compared to 3.42 and 2.51, respectively, for the no chemotherapy patients. Average total healthcare costs ranged from US$85,422 for no chemotherapy to US$168,628 for FOLFOX. Incremental cost-effectiveness ratios (ICER) for 5-FU versus no chemotherapy were US$17,131 per life-year gained and US$20,058 per QALY gained. ICERs for FOLFOX versus 5-FU were US$139,646 per life-year gained and US$188,218 per QALY gained. Results appear to be sensitive to age, suggesting that FOLFOX performs better for patients 65-69 and 80+ years old while 5-FU appears most effective and cost effective for the age groups 70-74 and 75-79 years. CONCLUSION FOLFOX appears more effective and cost effective than other strategies for colon cancer treatment of older patients. Results were sensitive to age, with ICERs exhibiting a U-shaped pattern.
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Affiliation(s)
- David R Lairson
- Division of Management, Policy and Community Health, School of Public Health, University of Texas Health Science Center at Houston, 1200 Herman Pressler Drive, Houston, TX, 77030, USA,
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Das D, Preet R, Mohapatra P, Satapathy SR, Kundu CN. 1,3-Bis(2-chloroethyl)-1-nitrosourea enhances the inhibitory effect of Resveratrol on 5-fluorouracil sensitive/resistant colon cancer cells. World J Gastroenterol 2013; 19:7374-7388. [PMID: 24259968 PMCID: PMC3831219 DOI: 10.3748/wjg.v19.i42.7374] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 03/22/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the mechanism of 5-fluorouracil (5-FU) resistance in colon cancer cells and to develop strategies for overcoming such resistance by combination treatment.
METHODS: We established and characterized a 5-FU resistance (5-FU-R) cell line derived from continuous exposure (25 μmol/L) to 5-FU for 20 wk in 5-FU sensitive HCT-116 cells. The proliferation and expression of different representative apoptosis and anti-apoptosis markers in 5-FU sensitive and 5-FU resistance cells were measured by the MTT assay and by Western blotting, respectively, after treatment with Resveratrol (Res) and/or 1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU). Apoptosis and cell cycle arrest was measured by 4',6'-diamidino-2-phenylindole hydrochloride staining and fluorescence-activated cell sorting analysis, respectively. The extent of DNA damage was measured by the Comet assay. We measured the visible changes in the DNA damage/repair cascade by Western blotting.
RESULTS: The widely used chemotherapeutic agents BCNU and Res decreased the growth of 5-FU sensitive HCT-116 cells in a dose dependent manner. Combined application of BCNU and Res caused more apoptosis in 5-FU sensitive cells in comparison to individual treatment. In addition, the combined application of BCNU and Res caused a significant decrease of major DNA base excision repair components in 5-FU sensitive cells. We established a 5-FU resistance cell line (5-FU-R) from 5-FU-sensitive HCT-116 (mismatch repair deficient) cells that was not resistant to other chemotherapeutic agents (e.g., BCNU, Res) except 5-FU. The 5-FU resistance of 5-FU-R cells was assessed by exposure to increasing concentrations of 5-FU followed by the MTT assay. There was no significant cell death noted in 5-FU-R cells in comparison to 5-FU sensitive cells after 5-FU treatment. This resistant cell line overexpressed anti-apoptotic [e.g., AKT, nuclear factor κB, FLICE-like inhibitory protein), DNA repair (e.g., DNA polymerase beta (POL-β), DNA polymerase eta (POLH), protein Flap endonuclease 1 (FEN1), DNA damage-binding protein 2 (DDB2)] and 5-FU-resistance proteins (thymidylate synthase) but under expressed pro-apoptotic proteins (e.g., DAB2, CK1) in comparison to the parental cells. Increased genotoxicity and apoptosis were observed in resistant cells after combined application of BCNU and Res in comparison to untreated or parental cells. BCNU increased the sensitivity to Res of 5-FU resistant cells compared with parental cells. Fifty percent cell death were noted in parental cells when 18 μmol/L of Res was associated with fixed concentration (20 μmol/L) of BCNU, but a much lower concentration of Res (8 μmol/L) was needed to achieve the same effect in 5-FU resistant cells. Interestingly, increased levels of adenomatous polyposis coli and decreased levels POL-β, POLH, FEN1 and DDB2 were noted after the same combined treatment in resistant cells.
CONCLUSION: BCNU combined with Res exerts a synergistic effect that may prove useful for the treatment of colon cancer and to overcome drug resistance.
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Reese ES, Onukwugha E, Hanna N, Seal BS, Mullins CD. Clinical and demographic characteristics associated with the receipt of chemotherapy treatment among 7951 elderly metastatic colon cancer patients. Cancer Med 2013; 2:907-15. [PMID: 24403264 PMCID: PMC3892395 DOI: 10.1002/cam4.143] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 08/31/2013] [Accepted: 09/02/2013] [Indexed: 12/25/2022] Open
Abstract
Among older individuals diagnosed with metastatic colon cancer (mCC) there is limited evidence available that describes the characteristics associated with advancing to second- and subsequent lines of treatment with chemotherapy/biologics. Our objective was to describe the trends and lines of treatment received among elderly mCC patients. Elderly beneficiaries diagnosed with mCC from 2003 to 2007 were identified in the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset. Beneficiaries were followed up until death or censoring. Treatment lines were classified in combinations of chemotherapies and biologics. Modified Poisson regression was used to predict receipt of lines of treatment. Analyses controlled for age, race/ethnicity, gender, marital status, state buy-in during diagnosis year, SEER-registry site, Charlson comorbidity index (CCI), poor performance indicators, surgery of primary site, and surgery of regional/distal sites. Among 7951 Medicare beneficiaries identified with mCC, 3266 initiated therapy. Of these, 1440 advanced to second-line treatment. Of these, 274 advanced to a subsequent-line treatment. Surgeries of the primary tumor site and of the regional/distal sites and marital status were the most significant variables associated with advancing through second- and subsequent-line treatments. Greater than 80 years of age, African American race, SEER-registry area, less than 6 months state buy-in assistance in mCC diagnosis year, and having poor performance indicators were inversely associated with receipt of second- or subsequent-line treatments. Among elderly individuals diagnosed with mCC, we identified demographic, clinical, and regional factors associated with receipt of second- and subsequent-line chemotherapy/biologics. Additional research is warranted to understand the role of physician versus patient preferences as well as geographic differences explaining why patients advance through lines of chemotherapy.
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Affiliation(s)
- Emily S Reese
- Pharmaceutical Health Services Research Department, School of Pharmacy, University of Maryland, Baltimore, Maryland
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Management of colon cancer: resource-stratified guidelines from the Asian Oncology Summit 2012. Lancet Oncol 2013; 13:e470-81. [PMID: 23117002 DOI: 10.1016/s1470-2045(12)70424-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Colon cancer is seen with increasing frequency in the Asia-Pacific region, and it is one of the most important causes of cancer mortality worldwide. This article reviews the available evidence for optimum management of colon cancer-in particular, with respect to screening and early detection of colon cancer, laparoscopic surgical treatment, adjuvant treatment of individuals with high-risk stage II and stage III cancer, palliative treatment of patients with metastatic disease, and management of resectable and potentially resectable metastases-and how these strategies can be applied in Asian countries with different levels of health-care resources and economic development, stratified by basic, limited, enhanced, and maximum resource levels.
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