Cost-Effectiveness Analysis of a Three-Drug Regimen Containing Bevacizumab for the Treatment of Recurrent Pediatric Medulloblastoma in China: Based on a COG Randomized Phase II Screening Trial.

Background: Medulloblastoma is the most common malignant brain tumor of childhood, accounting for 6 to 7 percent of all childhood CNS tumors. The purpose of this study was to evaluate the economic efficacy of a bevacizumab combined with temozolomide + irinotecan regimen for the treatment of recurrent pediatric medulloblastoma in China. Methods: The data analyzed were from a randomized phase II screening trial that showed an improved survival benefit in child patients with recurrent medulloblastoma treated with a T+I+B combination regimen. A Markov model is constructed to estimate the incremental cost-effectiveness ratio (ICER) from the perspective of Chinese society. The uncertainty in the model is solved by one-way certainty and probabilistic sensitivity analysis. Results: Our base case analysis showed that the total costs of treatment increased from $8,786.403 to $27,603.420 with the combination bevacizumab vs. the two-agent chemotherapy regimen. Treatment with T+I+B combination therapy was associated with an increase in effectiveness of 0.280 QALYs from 0.867 to 1.147 QALYs T+I regimen. The incremental cost-effectiveness ratio was $67,203.632/QALY, which exceeded our pre-specified willingness-to-pay threshold ($38,136.26/QALY). Cost changes associated with grade 3-4 AE management, tests used, or hospitalization costs had little effect on the ICER values predicted by sensitivity analysis. Conclusions: Taken together, the results of this study suggest that the combination of bevacizumab with temozolomide and irinotecan is not a cost-effective option from the perspective of Chinese payers as a first-line treatment option for children with recurrent medulloblastoma in China.

Real-World Cost-Effectiveness of First-Line Gemcitabine Plus Nab-Paclitaxel vs FOLFIRINOX in Patients With Advanced Pancreatic Cancer.

BACKGROUND: There are no randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and fluorouracil, folinic acid, irinotecan, oxaliplatin (FOLFIRINOX) for advanced pancreatic cancer (APC). Although it is well known that RCT-based efficacy often does not translate to real-world effectiveness, there is limited literature investigating comparative cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC. We aimed to examine the real-world cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC in Ontario, Canada. METHODS: This study compared patients treated with first-line Gem-Nab or FOLFIRINOX for APC in Ontario from April 2015 to March 2019. Patients were linked to administrative databases. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring, and discounted at 1.5%. Incremental cost-effectiveness ratio and net monetary benefit were computed to estimate cost-effectiveness from the public health-care payer's perspective. Sensitivity analysis was conducted using the propensity score matching method. RESULTS: A total of 1988 patients were identified (Gem-Nab: n = 928; FOLFIRINOX: n = 1060). Mean survival was lower for patients in the Gem-Nab than the FOLFIRINOX group (0.98 vs 1.26 life-years; incremental effectiveness = -0.28 life-years [95% confidence interval = -0.47 to -0.13]). Patients in the Gem-Nab group incurred greater mean 5-year total costs (Gem-Nab: $103 884; FOLFIRINOX: $101 518). Key cost contributors include ambulatory cancer care, acute inpatient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it was less effective and more costly. Results from the sensitivity analysis were similar. CONCLUSIONS: Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore not considered cost-effective at commonly accepted willingness-to-pay thresholds.

Assessment of Drug-drug Interaction and Optimization in Capecitabine and Irinotecan Combination Regimen using a Physiologically Based Pharmacokinetic Model.

Capecitabine and irinotecan (CPT-11) combination regimen (XELIRI) is used for colorectal cancer treatment. Capecitabine is metabolized to 5-fluorouracil (5-FU) by three enzymes, including carboxylesterase (CES). CES can also convert CPT-11 to 7-ethyl-10-hydroxycamptotecin (SN-38). CES is involved in the metabolic activation of both capecitabine and CPT-11, and it is possible that drug-drug interactions occur in XELIRI. Here, a physiologically based pharmacokinetic (PBPK) model was developed to evaluate drug-drug interactions. Capecitabine (180 mg/kg) and CPT-11 (180 mg/m2) were administered to rats, and blood (250 µL) was collected from the jugular vein nine times after administration. Metabolic enzyme activities and Ki values were calculated through in vitro experiments. The plasma concentration of 5-FU in XELIRI was significantly decreased compared to capecitabine monotherapy, and metabolism of capecitabine by CES was inhibited by CPT-11. A PBPK model was developed based on the in vivo and in vitro results. Furthermore, a PBPK model-based simulation was performed with the capecitabin dose ranging from 0 to 1000mol/kg in XELIRI, and it was found that an approximately 1.7-fold dosage of capecitabine was required in XELIRI for comparable 5-FU exposure with capecitabine monotherapy. PBPK model-based simulation will contribute to the optimization of colorectal cancer chemotherapy using XELIRI.

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.

Conversion to biosimilar pegfilgrastim-cbqv enables budget-neutral access to FOLFIRINOX treatment for metastatic pancreatic cancer.

Aim: To estimate the cost-savings from conversion to biosimilar pegfilgrastim-cbqv that can be reallocated to provide budget-neutral expanded access to FOLFIRINOX in patients with metastatic pancreatic cancer. Methods: Simulation modeling in a panel of 2500 FOLFIRINOX-treated patients, using varying treatment duration (1-12 cycles) and conversion rates (10-100%), to estimate cost-savings and additional FOLFIRINOX treatment that could be budget neutral. Results: In a 2500-patient panel at 100% conversion, savings of US$6,907.41 per converted patient over 12 cycles of prophylaxis translate to US$17.3 million and could provide 72,273 additional FOLFIRINOX doses or 6023 full 6-month regimens. Conclusion: Conversion to biosimilar CIN/FN prophylaxis can generate significant cost-savings and provide budget-neutral expanded access to FOLFIRINOX treatment for patients with metastatic pancreatic cancer.

Lay abstract Pegfilgrastim is used to prevent low white blood cell count in patients receiving chemotherapy. Comparable to a generic version of a drug, a biosimilar is a follow-on version of a biologic treatment. The authors calculated the savings from using biosimilar pegfilgrastim in a hypothetical group of 2500 patients with metastatic pancreatic cancer and then computed the number of additional doses of FOLFIRINOX chemotherapy that could be purchased with those savings. Using biosimilar pegfilgrastim for 12 cycles could save US$6,907.41 per patient. If all 2500 patients were treated with biosimilar pegfilgrastim, US$17.3 million could be saved. This could provide 72,273 additional FOLFIRINOX doses. Biosimilar pegfilgrastim can generate significant savings to purchase chemotherapy for additional patients cost-free.

Improved Assessment of Response Status in Patients with Pancreatic Cancer Treated with Neoadjuvant Therapy using Somatic Mutations and Liquid Biopsy Analysis.

PURPOSE: To evaluate somatic mutations, circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in patients with Pancreatic ductal adenocarcinoma (PDAC) with pathologic complete response (pCR) to neoadjuvant therapy (NAT) and find their associations with outcome. EXPERIMENTAL DESIGN: Thirty-six patients with PDAC with pCR were identified from 2009 to 2017. Macrodissection was performed on resected specimens to isolate DNA from 332 regions of interest including fibrosis, normal duct, normal parenchyma, and undefined ductal cells (UDCs). Cell-free DNA and CTCs were also extracted. Next-generation sequencing was used to detect mutations of KRAS, CDKN2A, SMAD4, TP53, GNAS, and BRAF. RESULTS: KRAS mutation was detected in UDCs and fibrosis while SMAD4, TP53, and GNAS were only seen in UDCs. Patients with TP53 mutation showed relatively worse overall survival (HR, 3.596, 95% CI, 0.855-15.130; P = 0.081). Five patients available for CTCs data were all positive for CTCs and seven of 16 patients with pCR were detected with ctDNA at surgery. We proposed a new concept of regression assessment combining genomic analysis of resected specimens and liquid biopsy data for PDAC, namely, molecular complete response (mCR). Three of six patients with mCR recurred as compared with six in 15 non-mCR patients. Seven of 15 non-mCR patients died during follow-up, while there was only one in six patients with mCR. CONCLUSIONS: This study first reports that somatic mutations, CTCs, and ctDNA existed even in patients with PDAC with pCR to NAT, which could possibly predict early recurrence and reduced survival. The current regression evaluation system of PDAC needs to be reassessed at a molecular level.

The economic burden of metastatic pancreatic cancer.

BACKGROUND: Objectives: Pancreatic cancer (PC) is a costly disease with a limited life-expectancy as it generally presents as an advanced, metastatic disease. Though current literature suggests cost varies by first line treatment, there is limited real-world knowledge about the economic burden of pancreatic cancer. This study describes the economic burden of pancreatic cancer patients overall and by observed first line treatments. METHODS: The IBM MarketScan databases were used to identify adult metastatic PC patients from January 1, 2010 through 3/31/2017. Those without other primary cancers, pregnancy, or prior PC treatment, and with 6 months of continuous enrollment prior to PC were included. Treatment patterns and healthcare utilization and expenditures were measured during the variable-length follow-up period. Continuous measures were presented as per patient per month (PPPM). RESULTS: A total of 6,360 patients met all inclusion criteria. Almost half (46.8%) of patients were untreated. Gemcitabine alone (15.6%) and FOLFIRINOX (11.4%) were the most commonly observed first line regimens. Treated patients incurred $17,513 PPPM (Gemcitabine alone) to $27,889 PPPM (FOLFIRINOX) during follow-up. Untreated patients incurred the highest unadjusted ($30,777 PPPM) and adjusted ($20,392 PPPM) cost. CONCLUSIONS: Metastatic PC patients incur a high economic burden driven by high utilization of healthcare resources, which varies by first line treatment. Also, the high proportion of untreated patients is alarming as these patients may be the most expensive of all patients. There is an unmet need in these patients for effective treatments that also reduce their economic burden.

Does a ketogenic diet as an adjuvant therapy for drug treatment enhance chemotherapy sensitivity and reduce target lesions in patients with locally recurrent or metastatic Her-2-negative breast cancer? Study protocol for a randomized controlled trial.

BACKGROUND: Recent studies have indicated that a ketogenic diet can be used as an adjuvant therapy to enhance sensitivity to chemotherapy and radiotherapy in cancer patients. However, there are no sufficient data and no consistent international treatment guidelines supporting a ketogenic diet as an adjuvant therapy for metastatic breast cancer. Therefore, this trial was designed to observe whether irinotecan with a ketogenic diet can promote sensitivity to chemotherapy and remit target lesions in locally recurrent or metastatic Her-2-negative breast cancer patients. METHODS/DESIGN: This trial aims to recruit 518 women with locally recurrent or metastatic breast cancer admitted to the Liaoning Cancer Hospital and Institute (Shenyang, China) in northeast China. All patients will be randomly assigned into the combined intervention group (n = 259) or the control group (n = 259), followed by treatment with irinotecan + ketogenic diet or irinotecan + normal diet, respectively. The primary endpoints are sensitivity to irinotecan and the objective response rate of target lesions; the secondary endpoints include quality of life scores (EORTC QLQ-C30), progression-free survival, overall survival time, incidence of adverse events, and cost-effectiveness. The endpoints will be evaluated at baseline (before drug administration), during treatment, 4 weeks after treatment completion, and every 3months (beginning 2 months after treatment completion). DISCUSSION: This trial attempts to investigate whether irinotecan treatment with a ketogenic diet for locally recurrent or metastatic breast cancer among women in northeast China can enhance the disease's sensitivity to chemotherapy and reduce target lesions. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR1900024597. Registered on 18 July 2019. Protocol Version: 1.1, 24 February 2017.

Treatment patterns and outcomes in pancreatic cancer: Retrospective claims analysis.

BACKGROUND: Pancreatic cancer represents the third leading cause of US cancer deaths, with median survival <1 year. The goal of this study was to describe systemic treatments, healthcare utilization and costs, and overall survival among patients with unresectable/metastatic disease. METHODS: This study used healthcare claims for commercial and Medicare Advantage enrollees diagnosed with pancreatic adenocarcinoma (at index date) during January 01 2010 to 31 May 2017. Included patients were aged ≥18 years, with continuous 6-month preindex enrollment. Patients were excluded by resectable disease, another primary cancer, or pregnancy. Cohorts were based on first-line (LOT1) chemotherapy regimen. RESULTS: Overall, 12 978 patients (mean age 70 years, 51% male) were included, among which 5610 (43%) received chemotherapy. Of those, 23% received gemcitabine monotherapy, 22% gemcitabine-nab paclitaxel, 22% FOLFIRINOX, 3% FOLFOX, and 29% received other regimens. Mean LOT1 duration was 112 days; 60% did not undergo subsequent lines of therapy. Moreover, 50% of patients had an emergency room visit and 45% were hospitalized during LOT1. Among treated and untreated patients, mean total 6-month costs were $52 101. We found that patients receiving FOLFIRINOX had the highest costs, whereas those who received gemcitabine monotherapy had the lowest. Median overall survival (mOS) was 335 days with any first-line treatment. FOLFIRINOX-treated patients had the highest mOS (492 days), whereas gemcitabine monotherapy-treated patients had the lowest (223 days). CONCLUSIONS: A large proportion (57%) of patients with unresectable/metastatic pancreatic cancer did not receive chemotherapy. Healthcare costs were higher for fluorouracil-based regimens, while lower for gemcitabine-based regimens. Survival rates were within expectations for advanced pancreatic cancer.

Sarcopenia supersedes subjective global assessment as a predictor of survival in colorectal cancer.

BACKGROUND: Sarcopenia, the presence of skeletal muscle mass depletion, can be objectively quantified, whereas subjective global assessment (SGA) is a widely utilized subjective instrument to assess nutritional status. Both the presence of sarcopenia and SGA-assessed malnutrition, in isolation, have been shown to be associated with worse overall survival in a wide range of cancers. However, there is no research evaluating the independent prognostic significance of both the presence of sarcopenia and malnutrition as part of the same analysis. We investigated the impact of sarcopenia on overall survival in colorectal cancer specifically controlling for malnutrition. METHODS: We examined a consecutive case series of 112 patients with colorectal cancer first seen at our institution between August 2012 and October 2017. Using computed tomography (CT) imaging, the cross-sectional area of muscles at the L3 vertebral level was measured and then divided by height squared to calculate skeletal muscle index (SMI). Sarcopenia was defined as SMI ≤38.5 cm2/m2 for women and ≤52.4 cm2/m2 for men. SGA assessments were completed within 2 weeks of CT imaging. The association of sarcopenia and malnutrition with overall survival was assessed using univariate and multivariate Cox regression analysis. RESULTS: Median age at presentation was 53.3 years. Sixty-six (58.9%) patients had metastatic disease at diagnosis. Using SMI, 46 (41.1%) patients were sarcopenic, while 66 (58.9%) were non-sarcopenic. Using SGA, 69 (61.6%) patients were assessed as well-nourished, while 43 (38.4%) were malnourished. Of 69 patients classified as well-nourished by SGA, 22 (31.9%) were sarcopenic. Similarly, of 43 patients categorized as malnourished by SGA, 19 (44.2%) were non-sarcopenic. On multivariate analysis, after adjusting for age, gender, tumor stage, BMI, treatment history and SGA, patients with sarcopenia had 3 times greater risk of mortality compared to those without sarcopenia (p = 0.001). The median survival of patients with both sarcopenia and malnutrition (n = 24) was 14.6 months (95% CI: 10.5 to 18.6) compared to the median survival of 25.9 months (95% CI: 7.8 to 44.0) in patients who were either sarcopenic or malnourished but not both (n = 41; p = 0.001). The median survival of patients who were non-sarcopenic and well nourished (n = 48; p = 0.001) was 38.6 months (95% CI: 25.6 to 51.6). CONCLUSIONS: The exploratory study suggests that presence of sarcopenia supersedes the presence of malnutrition as a predictor of survival in colorectal cancer. Co-existence of sarcopenia and malnutrition is associated with worse survival in colorectal cancer compared to just one of those conditions being present. Prospective studies with large sample sizes are needed to confirm these findings.

Irinotecan and vincristine for the treatment of refractory desmoplastic small round cell tumor in a developing country: a case report.

INTRODUCTION: Desmoplastic small round cell tumor is an extremely rare and aggressive cancer that affects mainly adolescents and young adults. Despite multiple therapeutic strategies, most patients have resistant disease with very poor survival rates. CASE PRESENTATION: We present a case of a 10-year-old Caucasian boy with a desmoplastic small round cell tumor refractory to conventional treatment who exhibited a good response to alternative treatment. With use of irinotecan and vincristine in association with radiation therapy, a reduction of 96.9% of the dimensions of the target lesions compared with the initial image was observed. CONCLUSION: This chemotherapy regimen, in association with radiation therapy, demonstrated efficacy for refractory desmoplastic small round cell tumor in our patient, and it is cost-effective.

FOLFIRINOX is a cost-effective combination chemotherapy in first-line for advanced pancreatic Cancer.

OBJECTIVES: The analysis was conducted to assess the effect of front-line combination chemotherapies on progression free survival (PFS). METHODS: The analysis was restricted to phase III randomized controlled trials (RCTs) in first-line therapy for advanced pancreatic cancer. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above phase III RCTs. We have also calculated differences in PFS between the different arms of each trial and the pharmacological costs necessary to get the benefit in PFS, for each trial. RESULTS: Our study evaluated 11 phase III randomized controlled trials (RCTs), including 4572 patients. Combining the costs of therapy with the measure of efficacy represented by the PFS, we have obtained 74.12 € per month of PFS gained for 5-FU, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX), 90.14 per month of PFS gained for gemcitabine and oxaliplatin (GEMOX) and 4708.70 € per month of PFS gained for the combination of gemcitabine plus nab-pacliatxel against gemcitabine alone. CONCLUSIONS: Combining pharmacological costs with the measure of efficacy represented by PFS, FOLFIRINOX is a cost-effective first-line for advanced pancreatic cancer.

Managing the economic impact of advanced pancreatic cancer.

Pancreatic cancer is typically diagnosed in the late stage of the disease, making it the fourth leading cause of cancer-related death in the United States. It is also one of the few cancers with an increasing incidence, particularly in the younger population. By 2030, it is expected to become the second leading cause of cancer-related death. Patients with pancreatic cancer encounter monthly medical costs 15 times higher than those without, with costs highest in the later stages of the disease. Treatments for pancreatic cancer include surgery (available to fewer than 20% of newly diagnosed patients) and, for advanced disease, chemotherapy with gemcitabine with nab-paclitaxel or FOLFIRINOX, which can increase overall survival (OS) by a few months. Economic and outcome analyses of clinical data find no significant difference in OS between the 2 regimens, although FOLFIRINOX carries a much higher rate of serious adverse effects, limiting its use to patients with good performance status. In 2017, the FDA approved immunotherapy for patients with microsatellite instability-high or mismatch repair-deficient solid tumors, which occurs in approximately 1% of pancreatic cancer diagnoses. Several immunotherapies and targeted therapies are currently in clinical trials and may significantly alter the trajectory of the disease. However, they typically cost more than $100,000 per year, putting significant strain on payers. Thus, it is important that payers plan now for the potential arsenal of new treatments and identify opportunities to manage their utilization as well as patients with the disease to contain costs.

Neoadjuvant FOLFIRINOX for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer: Results of a Decision Analysis.

BACKGROUND: The effectiveness and cost-effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost-effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM). MATERIALS AND METHODS: We performed a decision-analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease-free survival, quality-adjusted life-years (QALYs), cost in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions. RESULTS: Model results found median overall survival (34.5/28.0/22.0 months) and disease-free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life-years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost-effective 92.4% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSION: Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost-effectiveness standpoint. Additional clinical data that further define the long-term effectiveness of nFOLFIRINOX are needed to confirm our results. IMPLICATIONS FOR PRACTICE: Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision-analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality-adjusted life years, overall survival, and incremental cost-effectiveness ratio.

Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics.

BACKGROUND: Oral drug formulations have several advantages compared to intravenous formulation. Apart from patient convenience and favorable pharmacoeconomics, they offer the possibility of frequent drug administration at home. In this study, we present a new oral irinotecan formulation designed as an enteric coated immediate release tablet which in pre-clinical studies has shown good exposure with low variability. METHODS: A phase I, dose escalating study to assess safety, tolerability, pharmacokinetics and efficacy of an oral irinotecan formulation and to establish the maximum tolerated dose (MTD). Each treatment cycle was once-daily irinotecan for 14 days followed by 1 week rest. RESULTS: 25 patients were included across four cohorts; 3 patients were included in cohort 1 (20 mg/m2), 7 patients were included in cohort 2 (30 mg/m2), 3 patients were included in cohort 3 (25 mg/m2) and 12 patients were included in cohort 4 (21 mg/m2). Median age was 67 years, 52% were performance status (PS) 0 while 48% were PS 1. Median number of prior therapies was 3 (range 1-6). MTD was established at 21 mg/m2. No responses were observed. Nine patients (36%) had stable disease (SD), lasting median 19 weeks (range 7-45 weeks). Among these five patients had previously received irinotecan. No grade 3/4 hematologic toxicities were reported. Totally six patients experienced grade 1/2 anemia, three patients had grade 1/2 leucopenia and 1 patient had grade 1 thrombocytopenia. Most common non-hematological grade 1 and 2 adverse events were nausea, fatigue, diarrhea, vomiting and cholinergic syndrome. Grade 3 toxicities included diarrhea, fatigue, nausea and vomiting, no grade 4 events were reported. PK data showed consistent daily exposures during treatment at days 1 and 14 and no drug accumulation. SN-38 interpatient variability was in the same range as after infusion. CONCLUSIONS: Oral irinotecan was generally well tolerated; side effects were manageable and similar in type to those observed with intravenous irinotecan. Hematological toxicities were few and only grade 1/2. In this heavily pre-treated patient population, oral irinotecan demonstrated activity even among patients previously treated with irinotecan.

Comparative Effectiveness and Safety of Monoclonal Antibodies (Bevacizumab, Cetuximab, and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: The last decade has seen the increasing use of biological medicines in combination with chemotherapy containing 5-fluorouracil/oxaliplatin or irinotecan for the treatment of metastatic colorectal cancer (mCRC). These combinations have resulted in increased progression-free survival (PFS) in patients with mCRC; however, there are remaining concerns over the extent of their effect on overall survival (OS). Published studies to date suggest no major differences between the three currently available monoclonal antibodies (MoAbs); however, there are differences in costs. In addition, there is rising litigation in Brazil in order to access these medicines as they are currently not reimbursed. OBJECTIVE: The aim was to investigate the comparative effectiveness and safety of three MoAbs (bevacizumab, cetuximab and panitumumab) associated with fluoropyrimidine-based chemotherapy regimens and compared to fluoropyrimidine-based chemotherapy alone in patients with mCRC, through an updated systematic review and meta-analysis of concurrent or non-concurrent observational cohort studies, to guide authorities and the judiciary. METHOD: A systematic review and meta-analysis was performed based on cohort studies published in databases up to November 2017. Effectiveness measures included OS, PFS, post-progression survival (PPS), Response Evaluation Criteria In Solid Tumors (RECIST), response rate, metastasectomy and safety. The methodological quality of the studies was also evaluated. RESULTS: A total of 21 observational cohort studies were included. There were statistically significant and clinically relevant benefits in patients treated with bevacizumab versus no bevacizumab mainly around OS, PFS, PPS and the metastasectomy rate, but not for the disease control rates. However, there was an increase in treatment-related toxicities and concerns with the heterogeneity of the studies. CONCLUSION: The results pointed to an advantage in favor of bevacizumab for OS, PFS, PPS, and metastasectomy. Although this advantage may be considered clinically modest, bevacizumab represents a hope for increased survival and a chance of metastasectomy for patients with mCRC. However, there are serious adverse events associated with its use, especially severe hypertension and gastrointestinal perforation, that need to be considered.

A population-based outcomes study of patients with metastatic gastric cancer receiving second-line chemotherapy: A nationwide health insurance database study.

PURPOSE: The survival benefit of second-line chemotherapy in patients with metastatic gastric cancer (MGC) has recently been established. We conducted a nationwide population-based outcomes study of patients with MGC receiving second-line chemotherapy to better understand real-world treatment patterns and outcomes. MATERIALS AND METHODS: Data were collected from the Health Insurance Review and Assessment Service database. We identified 509 newly diagnosed patients with MGC in 2010 who received second-line chemotherapy. These patients were divided into three groups for analyses: Group A comprised all patients who received second-line chemotherapy (N = 509); Group B comprised those who received fluoropyrimidine (Fp) plus platinum as first-line treatment, followed by irinotecan-based or taxane-based regimens as second-line chemotherapy (N = 284); and Group C comprised those who received Fp plus cisplatin as first-line treatment, followed by 5-fluorouracil (5-FU)/oxaliplatin, irinotecan-based, or taxane-based regimens as second-line chemotherapy (N = 184). RESULTS: Among patients who received first-line chemotherapy, 47.2% (509/1,078) continued to receive second-line chemotherapy. The most commonly used second-line chemotherapy regimens were 5-FU/irinotecan, 5-FU/oxaliplatin, and docetaxel. The median overall survival (OS) of all 509 patients was 5.2 months. The time from the start date of first-line chemotherapy to the start date of second-line chemotherapy > 6.1 months was an independent prognostic factor for improved OS. The type of chemotherapy regimen was not a significant factor affecting OS. CONCLUSION: The findings provide a better understanding of second-line treatment patterns and outcomes in patients with MGC and will help guide treatment decisions in real-world clinical practice.

Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Análisis de impacto presupuestal de 21 tecnologías para el manejo quimioterapéutico del cáncer en Colombia / Budget impact analysis of 21 technologies for the chemotherapeutic management of cancer in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) de los medicamentos quimioterapéuticos para el tratamiento de cáncer en Colombia, se desarrolló en el marco del mecanismo técnicocientífico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. La quimioterapia tiene un gran impacto en el tratamiento oncológico, la cual es indispensable por su valor terapéutico en varios tipos de cáncer. Esta tecnología puede ser usada sola o junto con otros tratamientos, tales como la cirugía o la radioterapia. La quimioterapia engloba a una gran variedad de fármacos y su objetivo es destruir las células tumorales con el fin de lograr la reducción de la enfermedad, los medicamentos empleados en este tipo de tratamiento se les denomina fármacos antineoplásicos. Cada tipo de tumor canceroso tiene una determinada sensibilidad a estos medicamentos, por lo tanto, es frecuente que el mismo fármaco se pueda emplear en el tratamiento de distintos tumores, variando las dosis o asociándolo a otros fármacos distintos. La quimioterapia puede ser administrada con fines curativos o para aliviar los síntomas y prolongar la supervivencia. La forma de administración de la quimioterapia es por ciclos y esto se logra alternando los periodos de tratamiento con periodos de descanso. Un ciclo es, por lo tanto, el periodo de administración del tratamiento y el de descanso hasta la siguiente administración. El objetivo de este análisis de impacto presupuestal (AIP) es estimar el esfuerzo financiero necesario para la adopción de la quimioterapia en el tratamiento de pacientes con cáncer en Colombia, en un horizonte temporal de tres años. Este documento está conformado por cuatro secciones: en la primera se identifican las tecnologías a evaluar, en la segunda sección se especifica la perspectiva, horizonte temporal y la población sobre la cual se realizó el AIP; en la sección tres se detallan los costos utilizados en el modelo, además de los escenarios planteados por los investigadores; por último, en la sección cuatro se exponen los resultados en los diferentes escenarios planteados. Este documento describe la metodología desarrollada para realizar el análisis de impacto presupuestal de 21 tecnologías para el manejo quimioterapéutico del cáncer en Colombia Este informe, sigue los lineamientos propuestos en el Manual para la Elaboración de Análisis de Impacto Presupuestal y en Manual de Participación y Deliberación publicados por IETS. A continuación, se muestran los detalles del ejercicio poblacional, de costeo y de la modelación de escenarios. Posteriormente, se presenta una interpretación de los resultados y los análisis de incertidumbre sobre los mismos. INSUMOS Y MÉTODOS: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal describiendo la siguiente información: Perspectiva: La perspectiva de este AIP es la del tercer pagador el cual en nuestro contexto es el Sistema General de Seguridad Social en Salud (SGSSS). Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de inclusión en el PBS en el año 1. Población total: Para el desarrollo de este AIP se parte de la población general afiliada al SGSSS colombiano sin distinción de sexo o edad. Las estimaciones de los años 1 a 3 se calcularon de acuerdo al comportamiento del crecimiento demográfico estimado por el DANE. RESULTADOS: Se muestra el resultado consolidado para las ventiun tecnologías objeto del Análisis de Impacto Presupuestal. La tecnología que genera un mayor impacto es Oxaliplatino, con un valor por persona de $2.363.250,76 usada en 3170 pacientes, para un total de $7.491.504.923,90. El Megestrol es la tecnología con menor impacto, con un costo por persona de $ 383.791,06 y siendo usada en 34 pacientes, tiene un valor total de $ 13.048.896,00. La tretinoina es la tecnología más económica por paciente, con un valor de $ 97.996,50, es usada en 242 personas para un total de $ 23.715.153,00. DISCUSIÓN: En la práctica actual existe un volumen amplio de recobros en el caso de estos medicamentos por usos UNIRS. En algunos casos, los cambios en el mercado farmacéutico, ya sea por el retiro de medicamentos o la llegada de ellos, hace que se modifique indicaciones ya existentes en los registros y que pueden llegar a impactar estos usos, por ejemplo aquellos casos en los que existe la indicación antineplásico y se cambian por indicaciones especificas, que pueden no considerar condiciones de salud de baja incidencia. Como se ha caracterizado con anterioridad, el mercado de tecnologías sanitarias que se encuentran incluidas al plan de beneficios en salud con cargo a la UPC difiere sustancialmente al mercado de tecnologías sanitarias aún no financiadas por dicho mecanismo. La existencia de las Empresas Administradoras de Planes de Beneficios (EAPB) presume la existencia de un actor que al maximizar su beneficio, es un buen negociador que en cumplimiento de los principios del SGSSS, llega a un precio de equilibrio que maximiza el beneficio social. En cambio, los medicamentos que son sujetos a recobros al ADRES presume un precio fuera de aquel nivel en donde se maximiza al beneficio social, en la medida que no hay una función clara de monopsonio que coteje y negocie un precio de adquisición. En algunos casos puede llegar asumir sobrecostos que las EAPB al ser intermediarias, no tienen incentivos para efectuar un adecuado control.