The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer.

Importance: Gemcitabine-nab-paclitaxel (GEMNAB) and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) both improve survival of patients with advanced pancreatic cancer when compared with single-agent gemcitabine in clinical trials. Objective: To describe changes in the survival of patients with advanced pancreatic cancer associated with sequential drug-funding approvals and to determine if there exist distinct patient populations for whom GEMNAB and FOLFIRINOX are associated with survival benefit. Design, Setting, and Participants: This population-based, retrospective cohort study examined all incident cases of advanced pancreatic cancer treated with first-line chemotherapy in Ontario, Canada (2008-2018) that were identified from the Cancer Care Ontario (Ontario Health) New Drug Funding Program database. Statistical analysis was performed from October 2020 to January 2021. Exposures: First-line chemotherapy for advanced pancreatic cancer. Main Outcomes and Measures: The main outcomes were the proportion of patients treated with each chemotherapy regimen over time and overall survival for each regimen. Cox proportional hazards regression models were used to compare overall survival between treatment regimens after adjustment for confounding variables, inverse probability of treatment weighting, and matching. Results: From 2008 to 2018, 5465 patients with advanced pancreatic cancer were treated with first-line chemotherapy in Ontario, Canada. The median (range) age of patients was 66.9 (27.8-93.4) years; 2447 (45%) were female; 878 (16%) had prior pancreatic resection, and 328 (6%) had prior adjuvant gemcitabine. During the time period when only gemcitabine and FOLFIRINOX were funded (2011-2015), 49% (929 of 1887) received FOLFIRINOX. When GEMNAB was subsequently funded (2015-2018), 9% (206 of 2347) received gemcitabine, 44% (1034 of 2347) received FOLFIRINOX, and 47% (1107 of 2347) received GEMNAB. The median overall survival increased from 5.6 months (95% CI, 5.1-6.0 months) in 2008 to 2011 to 6.9 months (95% CI, 6.5-7.4 months) in 2011 to 2015 to 7.6 months (95% CI, 7.1-8.0 months) in 2015 to 2018. Patients receiving FOLFIRINOX were younger and healthier than patients receiving GEMNAB. After adjustment and weighting, FOLFIRINOX was associated with better overall survival than GEMNAB (hazard ratio [HR], 0.75 [95% CI, 0.69-0.81]). In analyses comparing patients treated with GEMNAB and gemcitabine, GEMNAB was associated with better overall survival (HR, 0.86 [95% CI, 0.78-0.94]). Conclusions and Relevance: This cohort study of patients with advanced pancreatic cancer receiving first-line palliative chemotherapy within a universal health care system found that drug funding decisions were associated with increased uptake of new treatment options over time and improved survival. Both FOLFIRINOX and GEMNAB were associated with survival benefits in distinct patient populations.

Cost-effectiveness analysis of FOLFIRINOX vs gemcitabine with nab-paclitaxel as adjuvant treatment for resected pancreatic cancer in the United States based on PRODIGE-24 and APACT trials.

BACKGROUND: Pancreatic cancer is associated with low median overall survival. Combination chemotherapy regimens FOLFIRINOX and gemcitabine with nab-paclitaxel (GemNab) are the new adjuvant treatment standards for resectable pancreatic cancer. PRODIGE-24 and APACT trials demonstrated superior clinical outcomes with FOLFIRINOX and GemNab, each vs gemcitabine monotherapy. OBJECTIVE: To evaluate the cost-effectiveness of FOLFIRINOX vs GemNab for resectable pancreatic cancer in adults from the U.S. payer perspective, in order to inform decision makers about which of these treatments is optimal. METHODS: A Markov model with 3 disease states (relapse free, progressive disease, and death) was developed. Cycle length was 1 month, and time horizon was 10 years. Transition probabilities were derived from PRODIGE-24 and APACT survival data. All cost and utility input parameters were obtained from published literature. Cost-effectiveness analysis was performed to obtain total costs, quality-adjusted life-years (QALYs), life-years (LYs), and incremental cost-effectiveness ratio (ICER). A 3% annual discount rate was applied to costs and outcomes. The effect of uncertainty on model parameters was assessed with 1-way and probabilistic sensitivity analysis (PSA). RESULTS: Our analysis estimated that the cost for FOLFIRINOX was $40,831 higher than GemNab ($99,669 vs. $58,837). Despite increased toxicity, FOLFIRINOX was associated with additional 0.18 QALYs and 0.25 LYs compared with GemNab (QALY: 1.65 vs. 1.47; LY: 2.09 vs. 1.84). The ICER for FOLFIRINOX vs GemNab was $226,841 per QALY and $163,325 per LY. FOLFIRINOX was not cost-effective at a willingness-to-pay (WTP) threshold of $200,000 per QALY, and this was confirmed by the PSA. CONCLUSIONS: Total monthly cost for FOLFIRINOX was approximately 1.7 times higher than GemNab. If the WTP threshold increases to or above $250,000 per QALY, FOLFIRINOX then becomes a cost-effective treatment option. DISCLOSURES: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors have no conflicts of interest to declare.

The Value of Survival Gains in Pancreatic Cancer from Novel Treatment Regimens.

BACKGROUND: Metastatic pancreatic cancer (mPC) is associated with low survival, with less than 10% of patients surviving 5 years. Recent therapies improve survival outcomes where few alternative therapies exist, but few economic analyses measure the value of survival gains attributable to new therapies. OBJECTIVE: To estimate the value of survival gains in advanced or mPC attributable to the introduction of novel treatment regimens. METHODS: Multivariate Cox proportional hazards models were used to estimate real-world survival gains associated with the introduction of gemcitabine (GEM) for patients diagnosed with stage IV or unstaged mPC in the Surveillance, Epidemiology, and End Results Program cancer registries. Then, evidence from clinical trials was used to evaluate the survival gains associated with nab-paclitaxel + gemcitabine (nP +GEM) and FOLFIRINOX (FFX) relative to GEM. The survival estimates and clinical trial evidence were used to calibrate an economic model and assess the cumulative value of survival gains in mPC to patients. Costs of treatment were calculated based on published cost-effectiveness studies. RESULTS: We estimated that the introduction of GEM in 1996 was associated with a hazard ratio of 0.920 (P < 0.05) and an increase in median survival from 3.1 to 4.5 months. Results suggested that the value of survival gains attributable to GEM equaled about $71,000 per patient, while the value attributable to nP + GEM was an additional $56,700. Estimates for the value of survival gains per patient, net of total incremental lifetime treatment costs (drugs, adverse events, and other costs), were $50,294 for GEM and an additional $31,900 for nP + GEM. Clinical trials and cost-effectiveness studies reported an overall survival gain from FFX that was larger than, but statistically similar to, nP + GEM and had greater risk of adverse events and total incremental costs. We estimated that the total value of survival gains to mPC patients, net of total costs, associated with GEM was up to $47.6 billion, and the additional values attributable to nP+GEM and FFX were up to $39.0 billion and $26.3 billion, respectively. CONCLUSIONS: Historically, mPC patients have faced high disease burden and had few treatment options. Treatments introduced since 1996 have led to improved survival, with varying costs associated with treatment and adverse events. Accounting for total incremental costs, the majority of the value of survival gains from GEM and nP+GEM was retained by mPC patients, highlighting the value of innovation in settings where survival is low and few alternative therapies exist. DISCLOSURES: Support for this research was provided by Celgene. Precision Health Economics was compensated by Celgene for work on this study. MacEwan is an employee of, and Yin is a consultant to, Precision Health Economics. Kaura and Khan are employees of Celgene. Study concept and design were contributed primarily by Yin and MacEwan, along with Kaura and Khan. MacEwan collected the data, and data interpretation was performed primarily by MacEwan and Yin, along with Kaura and Khan. The manuscript was written and revised by MacEwan, Yin, Kaura, and Khan.

Topotecan, pegylated liposomal doxorubicin hydrochloride, paclitaxel, trabectedin and gemcitabine for advanced recurrent or refractory ovarian cancer: a systematic review and economic evaluation.

BACKGROUND: Ovarian cancer is the fifth most common cancer in the UK, and the fourth most common cause of cancer death. Of those people successfully treated with first-line chemotherapy, 55-75% will relapse within 2 years. At this time, it is uncertain which chemotherapy regimen is more clinically effective and cost-effective for the treatment of recurrent, advanced ovarian cancer. OBJECTIVES: To determine the comparative clinical effectiveness and cost-effectiveness of topotecan (Hycamtin(®), GlaxoSmithKline), pegylated liposomal doxorubicin hydrochloride (PLDH; Caelyx(®), Schering-Plough), paclitaxel (Taxol(®), Bristol-Myers Squibb), trabectedin (Yondelis(®), PharmaMar) and gemcitabine (Gemzar(®), Eli Lilly and Company) for the treatment of advanced, recurrent ovarian cancer. DATA SOURCES: Electronic databases (MEDLINE(®), EMBASE, Cochrane Central Register of Controlled Trials, Health Technology Assessment database, NHS Economic Evaluations Database) and trial registries were searched, and company submissions were reviewed. Databases were searched from inception to May 2013. METHODS: A systematic review of the clinical and economic literature was carried out following standard methodological principles. Double-blind, randomised, placebo-controlled trials, evaluating topotecan, PLDH, paclitaxel, trabectedin and gemcitabine, and economic evaluations were included. A network meta-analysis (NMA) was carried out. A de novo economic model was developed. RESULTS: For most outcomes measuring clinical response, two networks were constructed: one evaluating platinum-based regimens and one evaluating non-platinum-based regimens. In people with platinum-sensitive disease, NMA found statistically significant benefits for PLDH plus platinum, and paclitaxel plus platinum for overall survival (OS) compared with platinum monotherapy. PLDH plus platinum significantly prolonged progression-free survival (PFS) compared with paclitaxel plus platinum. Of the non-platinum-based treatments, PLDH monotherapy and trabectedin plus PLDH were found to significantly increase OS, but not PFS, compared with topotecan monotherapy. In people with platinum-resistant/-refractory (PRR) disease, NMA found no statistically significant differences for any treatment compared with alternative regimens in OS and PFS. Economic modelling indicated that, for people with platinum-sensitive disease and receiving platinum-based therapy, the estimated probabilistic incremental cost-effectiveness ratio [ICER; incremental cost per additional quality-adjusted life-year (QALY)] for paclitaxel plus platinum compared with platinum was £24,539. Gemcitabine plus carboplatin was extendedly dominated, and PLDH plus platinum was strictly dominated. For people with platinum-sensitive disease and receiving non-platinum-based therapy, the probabilistic ICERs associated with PLDH compared with paclitaxel, and trabectedin plus PLDH compared with PLDH, were estimated to be £25,931 and £81,353, respectively. Topotecan was strictly dominated. For people with PRR disease, the probabilistic ICER associated with topotecan compared with PLDH was estimated to be £324,188. Paclitaxel was strictly dominated. LIMITATIONS: As platinum- and non-platinum-based treatments were evaluated separately, the comparative clinical effectiveness and cost-effectiveness of these regimens is uncertain in patients with platinum-sensitive disease. CONCLUSIONS: For platinum-sensitive disease, it was not possible to compare the clinical effectiveness and cost-effectiveness of platinum-based therapies with non-platinum-based therapies. For people with platinum-sensitive disease and treated with platinum-based therapies, paclitaxel plus platinum could be considered cost-effective compared with platinum at a threshold of £30,000 per additional QALY. For people with platinum-sensitive disease and treated with non-platinum-based therapies, it is unclear whether PLDH would be considered cost-effective compared with paclitaxel at a threshold of £30,000 per additional QALY; trabectedin plus PLDH is unlikely to be considered cost-effective compared with PLDH. For patients with PRR disease, it is unlikely that topotecan would be considered cost-effective compared with PLDH. Randomised controlled trials comparing platinum with non-platinum-based treatments might help to verify the comparative effectiveness of these regimens. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003555. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Health-related quality of life and cost comparison of adjuvant capecitabine versus 5-fluorouracil/leucovorin in stage III colorectal cancer patients.

PURPOSE: The purpose of this study was to compare health-related quality of life (HRQoL) and costs associated with 2 adjuvant chemotherapy regimens [capecitabine-based therapy versus 5-fluorouracil/leucovorin (5-FU/LV)-based therapy] in stage III colorectal cancer patients. METHODS: We conducted a prospective, open-label, observational, multicenter study from July 2008 to July 2011. The European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires was used to assess HRQoL before, during, and after treatment. The direct and indirect costs of adjuvant treatment were estimated from a specially prepared questionnaire, the National Health Insurance Research Database, and other published sources. We used propensity scoring to match samples between groups and performed multivariate analyses to adjust for differences in patient demographics and clinical characteristics. RESULTS: A total of 497 patients were enrolled, and 356 completed the surveys. Following propensity score matching, 239 patients were included in the analysis (122 in the capecitabine-based group, 117 in the 5-FU/LV-based group). Global HRQoL scores did not differ significantly between the two groups. However, compared to patients in the 5-FU/LV-based group, patients in the capecitabine-based group had less nausea and vomiting (mid-term, P = 0.024; final, P = 0.013), appetite loss (mid-term, P < 0.0001; final, P = 0.001), and fewer side effects from chemotherapy (mid-term, P = 0.017). In addition, the monthly cost of capecitabine-based therapy was lower than those of 5-FU/LV-based therapy [NT$31,895.46 (US$1063.18) vs. NT$79,159.24 (US$2638.64) per patient]. CONCLUSIONS: Capecitabine is a reasonable alternative and cost-effective treatment option under current conditions for patients with stage III colorectal cancer.

Cost-effectiveness analysis of adjuvant chemotherapies in patients presenting with gastric cancer after D2 gastrectomy.

BACKGROUND: To analyze and compare the economic outcomes of adjuvant chemotherapy with capecitabine plus oxaliplatin (referred to as the XELOX strategy) and of S-1 (the S-1 strategy) for gastric cancer patients after D2 gastrectomy. METHODS: A Markov model was developed to simulate the lifetime disease course associated with stage II or III gastric cancer after D2 gastrectomy. The lifetime quality-adjusted life years (QALYs), associated costs, and incremental cost-effectiveness ratios (ICERs) were estimated. The clinical data were derived from the results of pilot studies. Direct costs were estimated from the perspective of the Chinese healthcare system, and the utility data were measured from end-point observations of Chinese patients. Sensitivity analyses were used to explore the impact of uncertainty on the model's outcomes. RESULTS: The combined adjuvant chemotherapy strategy with XELOX yielded the greatest increase in QALYs over the course of the disease (8.1 QALYs compared with 7.8 QALYs for the S-1 strategy and 6.2 for surgery alone). The incremental cost per QALY gained using the XELOX strategy was significantly lower than that for the S-1 strategy ($3,502 vs. $6,837, respectively). The results were sensitive to the costs of oxaliplatin and the hazard ratio of relapse-free survival. CONCLUSION: The observations reported herein suggest that adjuvant therapy with capecitabine plus oxaliplatin is a highly cost-effective strategy and more favorable treatment option than the S-1 strategy in patients with stage II or III gastric cancer who have undergone D2 gastrectomy.

Cost-effectiveness analysis of colon cancer treatments from MOSIAC and No. 16968 trials.

AIM: To compare XELOX and FOLFOX4 as colon cancer adjuvant chemotherapy based on MOSAIC and No. 16968 trails from Chinese cost-effectiveness perspective. METHODS: A decision-analytic Markov model was developed to compare the FOLFOX4 and XELOX regimens based MOSAIC and No. 16968 trial. Five states were included in our Markov model: well (state 1), minor toxicity (state 2), major toxicity (state 3), quitting adjuvant chemotherapy (state 4), and death due to adjuvant chemotherapy (state 5). Transitions among the 5 states were assumed to be Markovian. Costs were calculated from the perspective of the Chinese health-care payer. The utility data were taken from published studies. Sensitivity analyses were used to explore the impact of uncertainty factors in this cost-effectiveness analysis. RESULTS: Total direct costs of FOLFOX4 and XELOX per patient were $19884.96 ± 4280.30 and $18113.25 ± 3122.20, respectively. The total fees related to adverse events per patient during the entire treatment were $204.75 ± 16.80 for the XELOX group, and $873.72 ± 27.60 for the FOLFOX4 group, and the costs for travel and absenteeism per patient were $18495.00 for the XELOX group and $21,352.68 for the FOLFOX4 group. The base-case analysis showed that FOLFOX4 was estimated to produce an additional 0.06 in quality adjusted life years (QALYs) at an additional cost of $3950.47 when compared to the XELOX regimen over the model time horizon. The cost per QALY gained was $8047.30 in the XELOX group, which was $900.98 less than in the FOLFOX4 group ($8948.28). The one way sensitivity analysis demonstrated that the utility for the well state and minor toxicity state greatly influenced the incremental cost-effectiveness ratio of FOLFOX4. CONCLUSION: In term of cost-comparison, XELOX is expected to dominate FOLFOX4 regimes; Therefore, XELOX provides a more cost-effective adjuvant chemotherapy for colon cancer patients in China.

Cost-effectiveness of aspirin adjuvant therapy in early stage colorectal cancer in older patients.

BACKGROUND & AIMS: Recent observational studies showed that post-operative aspirin use reduces cancer relapse and death in the earliest stages of colorectal cancer. We sought to evaluate the cost-effectiveness of aspirin as an adjuvant therapy in Stage I and II colorectal cancer patients aged 65 years and older. METHODS: Two five-state Markov models were constructed separately for Stage I and II colorectal cancer using TreeAge Pro 2014. Two hypothetical cohorts of 10,000 individuals at a starting age of 65 years and with colorectal cancer in remission were put through the models separately. Cost-effectiveness of aspirin was evaluated against no treatment (Stage I and II) and capecitabine (Stage II) over a 20-year period from the United States societal perspective. Extensive one-way sensitivity analyses and multivariable Probabilistic Sensitivity Analyses (PSA) were performed. RESULTS: In the base case analyses, aspirin was cheaper and more effective compared to other comparators in both stages. Sensitivity analyses showed that no treatment and capecitabine (Stage II only) can be cost-effective alternatives if the utility of taking aspirin is below 0.909, aspirin's annual fatal adverse event probability exceeds 0.57%, aspirin's relative risk of disease progression is 0.997 or more, or when capecitabine's relative risk of disease progression is less than 0.228. Probabilistic Sensitivity Analyses (PSA) further showed that aspirin could be cost-effective 50% to 80% of the time when the willingness-to-pay threshold was varied from USD 20,000 to USD 100,000. CONCLUSION: Even with a modest treatment benefit, aspirin is likely to be cost-effective in Stage I and II colorectal cancer, thus suggesting a potential unique role in secondary prevention in this group of patients.

Cost-utility analysis of the newly recommended adjuvant chemotherapy for resectable gastric cancer patients in the 2011 Chinese National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Gastric Cancer.

BACKGROUND: Postoperative adjuvant chemotherapy with capecitabine and oxaliplatin was first recommended for resectable gastric cancer patients in the 2011 Chinese National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Gastric Cancer, but the economic influence of this therapy in China is unknown. OBJECTIVE: The aim of the present study was to determine the cost-effectiveness of adjuvant chemotherapy with capecitabine and oxaliplatin after a gastrectomy with extended (D2) lymph-node dissection, compared with a D2 gastrectomy alone, for patients with stage II-IIIB gastric cancer. METHODS: On the basis of data from the CLASSIC trial, a Markov model was created to determine economic and clinical data for patients in the chemotherapy and surgery group (CSG) and the surgery-only group (SOG). The costs, presented in 2010 US dollars and estimated from the perspective of the Chinese health-care system, were obtained from the published literature and the local health system. The utilities were based on published literature. Costs, life years (LYs), quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. A lifetime horizon and a 3 % annual discount rate were used. One-way and probabilistic sensitivity analyses were performed. RESULTS: For the base case, the CSG compared with SOG would increase LYs and QALYs in a 3-, 5-, 10- or 30-year time horizon (except the QALYs at 3 or 5 years). In the short run (such as in 3 or 5 years), the medical costs would increase owing to adjuvant chemotherapy of capecitabine plus oxaliplatin after D2 gastrectomy, but in the long run the costs would decline. The ICERs suggested that the SOG was dominant at 3 or 5 years and the CSG was dominant at 10 or 30 years. The one-way sensitivity analysis showed that the utility of disease-free survival for 1-10 years for the SOG and the cost of oxaliplatin were the most influential parameters. The probabilistic sensitivity analysis predicted a 98.6 % likelihood that the ICER for the CSG would be less than US$13,527/QALY (three times the per capita gross domestic product of China). CONCLUSION: For patients in China with resectable disease, our results suggest that adjuvant chemotherapy with capecitabine plus oxaliplatin after a D2 gastrectomy is cost-saving and dominant in the long run on the basis of a current clinical trial, compared with treatment with a D2 gastrectomy alone.

Economic evaluation of first-line adjuvant chemotherapies for resectable gastric cancer patients in China.

BACKGROUND: First-line postoperative adjuvant chemotherapies with S-1 and capecitabine and oxaliplatin (XELOX) were first recommended for resectable gastric cancer patients in the 2010 and 2011 Chinese NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer; however, their economic impact in China is unknown. OBJECTIVE: The aim of this study was to compare the cost-effectiveness of adjuvant chemotherapy with XELOX, with S-1 and no treatment after a gastrectomy with extended (D2) lymph-node dissection among patients with stage II-IIIB gastric cancer. METHODS: A Markov model, based on data from two clinical phase III trials, was developed to analyse the cost-effectiveness of patients in the XELOX group, S-1 group and surgery only (SO) group. The costs were estimated from the perspective of Chinese healthcare system. The utilities were assumed on the basis of previously published reports. Costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICER) were calculated with a lifetime horizon. One-way and probabilistic sensitivity analyses were performed. RESULTS: For the base case, XELOX had the lowest total cost ($44,568) and cost-effectiveness ratio ($7,360/QALY). The relative scenario analyses showed that SO was dominated by XELOX and the ICERs of S-1 was $58,843/QALY compared with XELOX. The one-way sensitivity analysis showed that the most influential parameter was the utility of disease-free survival. The probabilistic sensitivity analysis predicted a 75.8% likelihood that the ICER for XELOX would be less than $13,527 compared with S-1. When ICER was more than $38,000, the likelihood of cost-effectiveness achieved by S-1 group was greater than 50%. CONCLUSIONS: Our results suggest that for patients in China with resectable disease, first-line adjuvant chemotherapy with XELOX after a D2 gastrectomy is a best option comparing with S-1 and SO in view of our current study. In addition, S-1 might be a better choice, especially with a higher value of willingness-to-pay threshold.

Cost analysis of adjuvant therapy with XELOX or FOLFOX4 for colon cancer.

AIM: XELOX and FOLFOX4 have both been recommended as adjuvant therapy for stage III colon cancer. This study compared the two regimens in terms of monetary costs, assuming equal efficacy of the therapies. METHOD: A retrospective financial audit was conducted of the medical records of patients treated with XELOX or FOLFOX4. All itemized expenses were classified as direct (chemotherapy, hospitalization, venous access and tests), related to adverse effects due to the adjuvant therapy, or societal (travel and time costs). The cost of supportive care was not included. RESULTS: XELOX involved less total cost to the patient than FOLFOX4 (a difference of US$2857.68), fewer costs related to adverse effects ($668.97), and less travel ($26.07) and time ($390.93) expenditure per patient. CONCLUSION: The results indicate that, overall, XELOX is a more affordable option than FOLFOX4 in China.

Unsupported off-label chemotherapy in metastatic colon cancer.

BACKGROUND: Newer systemic therapies have the potential to decrease morbidity and mortality from metastatic colorectal cancer, yet such therapies are costly and have side effects. Little is known about their non-evidence-based use. METHODS: We conducted a retrospective cohort study using commercial insurance claims from UnitedHealthcare, and identified incident cases of metastatic colon cancer (mCC) from July 2007 through April 2010. We evaluated the use of three regimens with recommendations against their use in the National Comprehensive Cancer Center Network Guidelines, a commonly used standard of care: 1) bevacizumab beyond progression; 2) single agent capecitabine as a salvage therapy after failure on a fluoropyridimidine-containing regimen; 3) panitumumab or cetuximab after progression on a prior epidermal growth factor receptor antibody. We performed sensitivity analyses of key assumptions regarding cohort selection. Costs from a payer perspective were estimated using the average sales price for the entire duration and based on the number of claims. RESULTS: A total of 7642 patients with incident colon cancer were identified, of which 1041 (14%) had mCC. Of those, 139 (13%) potentially received at least one of the three unsupported off-label (UOL) therapies; capecitabine was administered to 121 patients and 49 (40%) likely received it outside of clinical guidelines, at an estimated cost of $718,000 for 218 claims. Thirty-eight patients received panitumumab and six patients (16%) received it after being on cetuximab at least two months, at an estimated cost of $69,500 for 19 claims. Bevacizumab was administered to 884 patients. Of those, 90 (10%) patients received it outside of clinical guidelines, at an estimated costs of $1.34 million for 636 claims. CONCLUSIONS: In a large privately insured mCC cohort, a substantial number of patients potentially received UOL treatment. The economic costs and treatment toxicities of these therapies warrant increased efforts to stem their use in settings lacking sufficient scientific evidence.

Pharmacoeconomic analysis of capecitabine versus 5-fluorouracil/leucovorin as adjuvant therapy for stage III colon cancer in Taiwan.

OBJECTIVES: To assess the cost-effectiveness of oral capecitabine compared with intravenous bolus 5-fluorouracil/leucovorin (5-FU/LV) in the adjuvant treatment of stage III colon cancer in Taiwan from payer (Bureau of National Health Insurance [BNHI]) perspectives. METHODS: A health state-transition model was developed to estimate the incremental costs and effectiveness of capecitabine versus 5-FU/LV. The time horizons studied were: treatment duration (24 weeks) plus 36 months, 48 months, 60 months, 120 months, and lifetime. Costs were expressed in Taiwanese new dollars (NT$). Clinical outcomes, medical resource use, and utilities were extracted from published sources. Unit costs were estimated from BNHI fee schedules, published sources, and local expert opinion. Outcomes and future costs were discounted at 3%. Cost-effectiveness was expressed as cost per quality-adjusted life-month (QALM). The effects of uncertainty were explored through a one-way sensitivity analysis. RESULTS: For the 24-week time period, drug acquisition costs were higher for capecitabine than 5-FU/LV (NT$114,405 vs. NT$4,904 per patient); however, these were offset by the higher administration costs of 5-FU/LV (NT$2,573 vs. NT$204,201 per patient). Overall direct costs for the 24-week treatment period were less with capecitabine than 5-FU/LV (NT$129,327 vs. NT$233,873 per patient). Cost savings with capecitabine were also evident when longer time horizons were considered. Over a lifetime, the projected survival benefit for capecitabine was 7 QALMs. CONCLUSIONS: From the perspectives of the BNHI and society in Taiwan, capecitabine not only saves costs but also improves health outcomes compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer.

XELOX in colorectal cancer: a convenient option for the future?

XELOX is a 3-weekly chemotherapy combination of oral capecitabine and intravenous oxaliplatin. The central hypothesis that led to its development was that it would provide a convenient and cost-effective alternative to intravenous fluorouracil-based chemotherapy doublets, without compromising on anti-tumor efficacy. Recently its role in colorectal cancer has become more established in both the metastatic and adjuvant setting. Ongoing investigation of XELOX continues in a number of directions: its combination with novel biological agents, its efficacy and safety in the elderly, and the development of biomarkers that can predict its anti-tumor effect. This article provides a comprehensive and up-to-date synopsis of all pertinent clinical studies detailing this regimen and its promise for the future.

Economic evaluation of capecitabine as adjuvant or metastatic therapy in colorectal cancer.

Capecitabine, an oral prodrug of 5-fluorouracil, is indicated for adjuvant treatment in patients with Dukes' C colon cancer and for subsequent lines in metastatic colorectal cancer. The aim of this article is to review the literature on the economics of capecitabine for the treatment of colon cancer. A systematic review was conducted to search for articles published from January 2003 to December 2009 that met the inclusion criteria. For abstracts that were considered acceptable, full-text articles were then reviewed. Of the 42 potential studies that were identified, 13 original studies (16 publications) met the inclusion criteria. To date, the economic evaluation literature has consistently projected or found that capecitabine is not only a cost-effective treatment for adjuvant or for metastatic colorectal cancer (i.e., providing good value for money) but, furthermore, would actually be cost saving in the majority of country settings.

Costs associated with capecitabine or 5-fluorouracil monotherapy after surgical resection in patients with colorectal cancer.

OBJECTIVE: To compare chemotherapy-related and total medical costs among patients with colorectal cancer (CRC) receiving capecitabine or 5-fluorouracil (5-FU) monotherapy after surgical resection. METHODS: This retrospective, claim-based study utilized the Thomson Reuters Market Scan(R) databases to identify 1,396 CRC patients who received capecitabine or 5-FU monotherapy within 90 days of surgical resection from 2003 through 2006. Propensity score matching addressed selection bias, and multivariate models estimated adjusted relative risks of treatment-related complications and medical costs of matched cohorts. RESULTS: Capecitabine users incurred USD 740 less in total direct medical costs (p = 0.003) and USD 785 less in chemotherapy-related costs (p < 0.0001) than 5-FU users. Although drug acquisition cost was higher for capecitabine than for 5-FU (USD 958 vs. USD 71, p < 0.0001), chemotherapy administration cost was lower (USD 76 vs. USD 1,062, p < 0.0001). The unadjusted (610 vs. 1,960 events per 1,000 person-months) and adjusted risks (47%) were lower for capecitabine than 5-FU for any complication, and specifically for bone marrow (67%), gastrointestinal (50%), and constitutional (41%) complications (p < 0.0001, all comparisons). CONCLUSIONS: Adjuvant capecitabine monotherapy was associated with lower total medical and chemotherapy-related costs than 5-FU. Reduced complications and costs associated with capecitabine administration offset the higher acquisition cost.

Cost-effectiveness analysis of capecitabine compared with bolus 5-fluorouracil/l-leucovorin for the adjuvant treatment of colon cancer in Japan.

OBJECTIVE: A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective. METHODS: Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses. RESULTS: In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product. CONCLUSION: This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Capecitabine and docetaxel combination for the treatment of breast cancer.

The management of breast cancer depends on the tumor and patient's characteristics. Anthracycline-based regimens have been proven to decrease the risk of relapse and prolong survival time in breast cancer. Taxanes have been incorporated not only into metastatic breast cancer but also into adjuvant regimens. Capecitabine, an oral fluoropyrimidine carbamate, has good single-agent activity and, together with docetaxel, demonstrated preclinical synergy and a survival benefit in metastatic breast cancer. Recent analyses show that capecitabine/docetaxel dosing flexibility for managing side effects does not compromise efficacy, and define this combination regimen as an important treatment option for its efficacy, tolerability and cost-effectiveness.

Budget impact model of adding erlotinib to a regimen of gemcitabine for the treatment of locally advanced, nonresectable or metastatic pancreatic cancer.

OBJECTIVE: The aim of this study was to determine the budget impact of adding erlotinib to a US health plan insurer's formulary as a combination therapy with gemcitabine for the treatment of nonresectable pancreatic cancer. METHODS: An Excel-based budget impact model was developed to evaluate the costs for National Comprehensive Cancer Network guideline-recommended treatment options for patients with locally advanced, nonresectable or metastatic pancreatic cancer from the perspective of a US managed care plan. The model compared treatment with gemcitabine alone and in combination with erlotinib, including the costs of treatment, adverse events (AEs), and administration. Inputs for the model were derived from the Surveillance, Epidemiology and End Results Cancer Registry, clinical trials, and publicly available sources and were varied in sensitivity analyses to identify influential inputs. The model addressed first-line use in a single indication and assumed that the proportion of patients aged >or=65 years in a managed care organization was the same as in the general population. The model did not account for patient copayments for oral medications, a factor that could lower a plan's overall cost further than estimated herein. RESULTS: For a hypothetical managed care plan with 500,000 members, the model estimated 43 newly diagnosed pancreatic cancer cases each year, of which 56% (n=24) would be treated with gemcitabine as first-line therapy. Assuming that erlotinib were added to the treatment regimen in 40% (n=10) of gemcitabine-treated patients for 15.7 weeks of therapy per patient, the expected 1-year cost in 2006 dollars would be US $466,700 compared with $346,700 had all patients been treated with gemcitabine alone. Administration costs accounted for 10% to 12% of total costs, while AE management costs made up 14% to 16% of total costs. These estimates corresponded to an incremental cost of $120,000, or $0.020 per member per month (PMPM). The results were relatively insensitive to drug costs, drug administration costs, and costs of treatment of AEs based on sensitivity analyses. CONCLUSIONS: In this analysis of the budget impact of adding to the health plan formulary erlotinib to a regimen of gemcitabine as first-line treatment of locally advanced, nonresectable or metastatic pancreatic cancer in the United States, the budget impact was $0.020 PMPM. The relatively low incidence of pancreatic cancer and the assumption of treating only 23% of these patients with erlotinib were likely the principal reasons for the low budgetary impact of erlotinib. In this model and using these reasonable assumptions, the results suggested that the incremental cost impact on a PMPM basis may be small.

Capecitabine, alone and in combination, in the management of patients with colorectal cancer: a review of the evidence.

Capecitabine, an oral prodrug of fluorouracil (5FU), has shown efficacy in terms of progression-free and overall survival at least equivalent to standard folinic acid (leucovorin)-modulated intravenous 5FU bolus regimens in patients with metastatic colorectal cancer. Moreover, capecitabine has demonstrated a better tolerability profile, producing a significantly lower occurrence of severe stomatitis than 5FU plus folinic acid regimens, making this drug particularly attractive for treating elderly patients. In addition, capecitabine can be combined with other active drugs such as irinotecan or oxaliplatin. Indeed, the combination of capecitabine plus oxaliplatin (XELOX regimen) now represents a new standard of care for the metastatic disease and is also under evaluation in the adjuvant setting. The combination of new biological drugs, such as bevacizumab, with the XELOX regimen was shown to further prolong the time to progression of metastatic disease, and might reduce the risk of recurrence for those with resected colon cancer with poor risk factors. Cost-effectiveness analyses have demonstrated that, despite higher acquisition costs, capecitabine appears to be more cost effective than standard treatments for the management of colorectal cancer patients.