Effects of Goshajinkigan (TJ-107) for oxaliplatin-induced peripheral neurotoxicity using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire in a Phase II, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The aim of the present study was to evaluate the efficacy of TJ-107 for oxaliplatin-induced peripheral neurotoxicity in prospective, multi-institutional, randomized, double-blind, placebo-controlled Phase II trials using the functional assessment of cancer therapy/gynecologic oncology group 12-item neurotoxicity questionnaire (FACT-GOG-NTX-12). PATIENTS AND METHODS: The patients who were registered to the Goshajinkigan oxaliplatin neurotoxicity evaluation study (UMIN000002211) were analyzed. A NTX-12 from the validated FACT/GOG-NTX-12 was assessed before treatment and at the end of every 2 cycles. RESULTS: The comparisons of the median scores for TJ-107 and the placebo at 8 and 26 weeks were as follows: numbness or tingling in the hands (P = 0.5820), numbness or tingling in the feet (P = 0.3236), feeling of discomfort in the hands (P = 0.8219), feeling of discomfort in the feet (P = 0.5361), joint pain or muscle cramps (P = 0.1974), feeling weak all over (P = 0.2771), trouble hearing (P = 0.2832), ringing or buzzing in ears (P = 0.1031), trouble buttoning buttons (P = 0.1653), trouble feeling the shape of small objects when held in hand (P = 0.2919), trouble walking (P = 0.5406), and pain in the hands or feet when exposed to cold temperatures (P = 0.1872). CONCLUSION: There might be no clinically significant difference between the use of TJ-107 and the severity and quality of life for patients treated with oxaliplatin.

The impact of socioeconomic status on stage at presentation, receipt of diagnostic imaging, receipt of treatment and overall survival in colorectal cancer patients.

Socioeconomic factors influence patterns of care in colorectal cancer. Our study investigates the impact of socioeconomic status (SES) on stage at presentation, receipt of diagnostic imaging, receipt of treatment and overall survival (OS) in a universal healthcare system. The Ontario Cancer Registry (OCR) was accessed to identify a cohort of patients diagnosed with colorectal adenocarcinoma from 2007 to 2016 in Ontario, Canada. SES was measured using median neighborhood income divided into quintiles (Q1-Q5; Q1 = lowest income). Logistic regression analyses were used to evaluate stage, imaging and treatment. Cox proportional hazards models were used to evaluate OS. All endpoints were adjusted for demographics and comorbidities with OS models also adjusting for stage, imaging and treatment. In total, 39 802 colon and 13 164 rectal patients were identified. Lower SES was associated with advanced stage at presentation in both cohorts (Q1 vs Q5: Colon odds ratio [OR] = 1.08, P = .046, rectal OR = 1.25, P < .0001). Lower SES colon patients were less likely to receive adjuvant oxaliplatin (Q1 vs Q5: OR = 0.78, P < .001) and all palliative chemotherapies studied including oxaliplatin (Q1 vs Q5: OR = 0.60, P < 0.0001), irinotecan (Q1 vs Q5: OR = 0.65, P < .0001), bevacizumab (Q1 vs Q5: OR = 0.70, P < .001), cetuximab (Q1 vs Q5: OR = 0.40, P = .0053) and panitumumab (Q1 vs Q5: OR = 0.54, P = .0036). In rectal patients, lower SES was associated with decreased receipt of rectal cancer resection for stages I-III (Q1 vs Q5: OR = 0.78, P < .001), adjuvant oxaliplatin (Q1 vs Q5: OR = 0.72, P = .0020) and palliative chemotherapies including oxaliplatin (Q1 vs Q5: OR = 0.59, P < .001), irinotecan (Q1 vs Q5: OR = 0.53, P < .001) and bevacizumab (Q1 vs Q5: OR = 0.71, P = .046). All survival models identified poorer OS for lower SES patients (total colorectal; Q1 vs Q5: Hazard ratio [HR] = 1.25, P < .0001). These findings suggest disparities persist even within universal healthcare.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Cost-effectiveness analysis of nab-paclitaxel plus gemcitabine versus folfirinox in the treatment of metastatic pancreatic cancer in china.

OBJECTIVES: Nab-paclitaxel (Abraxane®) plus gemcitabine (AG) and Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) have shown significant clinical benefit and been widely used as 1st-line treatment of metastatic pancreatic cancer (mPC) in China. This study aims to compare the cost-effectiveness of AG versus FOLFIRINOX regimen for the treatment of mPC patients in China. METHODS: Markov model was developed with a lifetime survival projection in Microsoft Excel® to simulate the progression of the mPC over time. The quality-adjusted life years (QALYs), resource consumption in the health care sector and incremental cost-effectiveness ratios (ICERs) were reported. Uncertainty was assessed by one-way and probabilistic sensitivity analyses. RESULTS: AG regimen provided an effectiveness of 1.35 QALY at an average cost of USD 22,300 whereas FOLFIRINOX regimen brought 0.82 QALY at a cost of USD 22,980 in lifetime horizon. Therefore, AG regimen was dominant with an ICER of USD -1300 compared with FOLFIRINOX regimen. AG arm generated less drug cost, medical cost, hospitalization cost, and end-of-life cost than FOLFIRINOX arm did. Sensitivity analyses confirmed the robustness of base case findings. CONCLUSIONS: AG is likely a cost-effective option for the 1st-line mPC treatment compared with FOLFIRINOX in China from the perspective of healthcare system.

Home-based chemotherapy for stage III colon cancer patients in Thailand: Cost-utility and budget impact analyses.

Home-based chemotherapy (HC) is a new treatment alternative to hospital-based chemotherapy treatment (IP) and is administered via portable intravenous pumps at the patient's home. HC reduces the demand for inpatient bed capacity in hospitals and reduces the cost of an infusion. This study takes a societal perspective while conducting the cost-utility and budget impact analyses (BIA) of HC and IP with an mFOLFOX6 regimen on patients with stage III colon cancer. We conducted a cost-utility analysis with a 6-month time horizon. The parameter inputs for the model were gathered from a retrospective cohort study on patients diagnosed with stage III colon cancer at Ramathibodi Hospital, Bangkok. The resource usage of HC and IP was determined based on medical records. The per-unit direct medical, home health service, and adverse events (AE) management costs were gathered from the standard cost list. The health outcome of treatment was measured in terms of quality-adjusted life years. Disutility related to AE was calculated. We conducted a sensitivity analysis for the uncertainty results and performed BIA based on the societal perspective on a 1-year time horizon. HC provided a cost-saving of $1,513.37 per patient for the period of treatment. Thus, assuming 526 patients per year, the use of HC could achieve a cumulative annual cost-saving of $828,436. HC is a cost-saving strategy compared to IP for stage III colon cancer treatment. We recommend that the service reimbursement should include national standardization in chemotherapy regimens as well as practice guidelines and protocols to prevent serious AEs.

The efficacy of oxaliplatin combination adjuvant chemotherapy for elderly patients with stage III colorectal cancer.

Now we are facing to aging society. We aimed to determine the long-term outcomes receiving adjuvant chemotherapy among elderly patients with stage III colorectal cancer. Elderly patients (≧65 years, n=91) diagnosed as stage III colorectal cancer and received adjuvant chemotherapy were retrieved from the database and classified into two groups according to whether the patient received monotherapy (n=65) or doublet therapy(n=26). Recurrence-free survival and overall survival were compared between the groups. To balance the essential variables, we conducted propensity score matching. After one-to-one propensity score matching, each group consisted of 22 patients. No significant difference was detected by comprehensive geriatric assessment 7. Overall survival was significantly longer in the monotherapy group. Adverse events occurred more frequently in the doublet therapy group. Monotherapy may improve the long-term outcome of elderly patients while the adverse events were less frequent.

Circulating tumor DNA guided adjuvant chemotherapy in stage II colon cancer (MEDOCC-CrEATE): study protocol for a trial within a cohort study.

BACKGROUND: Accurate detection of patients with minimal residual disease (MRD) after surgery for stage II colon cancer (CC) remains an urgent unmet clinical need to improve selection of patients who might benefit form adjuvant chemotherapy (ACT). Presence of circulating tumor DNA (ctDNA) is indicative for MRD and has high predictive value for recurrent disease. The MEDOCC-CrEATE trial investigates how many stage II CC patients with detectable ctDNA after surgery will accept ACT and whether ACT reduces the risk of recurrence in these patients. METHODS/DESIGN: MEDOCC-CrEATE follows the 'trial within cohorts' (TwiCs) design. Patients with colorectal cancer (CRC) are included in the Prospective Dutch ColoRectal Cancer cohort (PLCRC) and give informed consent for collection of clinical data, tissue and blood samples, and consent for future randomization. MEDOCC-CrEATE is a subcohort within PLCRC consisting of 1320 stage II CC patients without indication for ACT according to current guidelines, who are randomized 1:1 into an experimental and a control arm. In the experimental arm, post-surgery blood samples and tissue are analyzed for tissue-informed detection of plasma ctDNA, using the PGDx elio™ platform. Patients with detectable ctDNA will be offered ACT consisting of 8 cycles of capecitabine plus oxaliplatin while patients without detectable ctDNA and patients in the control group will standard follow-up according to guideline. The primary endpoint is the proportion of patients receiving ACT when ctDNA is detectable after resection. The main secondary outcome is 2-year recurrence rate (RR), but also includes 5-year RR, disease free survival, overall survival, time to recurrence, quality of life and cost-effectiveness. Data will be analyzed by intention to treat. DISCUSSION: The MEDOCC-CrEATE trial will provide insight into the willingness of stage II CC patients to be treated with ACT guided by ctDNA biomarker testing and whether ACT will prevent recurrences in a high-risk population. Use of the TwiCs design provides the opportunity to randomize patients before ctDNA measurement, avoiding ethical dilemmas of ctDNA status disclosure in the control group. TRIAL REGISTRATION: Netherlands Trial Register: NL6281/NTR6455 . Registered 18 May 2017, https://www.trialregister.nl/trial/6281.

Real-World Assessment of Health Care Costs for Patients with Metastatic Pancreatic Cancer Following Initiation of First-Line Chemotherapy.

BACKGROUND: Management of metastatic pancreatic ductal adenocarcinoma (mPDA) places a significant financial burden on the U.S. health care system because of such factors as treatment with multidrug chemotherapy regimens, management of chemotherapy-related adverse events, and disease- or treatment-related hospitalizations. Depending on functional status, first-line chemotherapy regimens that are guideline recommended include nab-paclitaxel with gemcitabine (AG) and FOLFIRINOX (FFX), the combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin. However, few previous studies have examined overall health care costs associated with mPDA management. OBJECTIVE: To describe health care costs following initiation of first-line treatment with AG or FFX among patients with mPDA. METHODS: Retrospective cohorts of first-line AG and FFX initiators were constructed from the MarketScan database (2014-2017). The index date was the date of first-line AG or FFX initiation. Included patients had insurance enrollment for 6 months before the index date. Total cumulative health care costs and costs from outpatient services, inpatient admissions, emergency department visits, chemotherapy administrations, and pharmacy dispensing were assessed within 12 months after the index date (i.e., 0-1, 0-2, …, 0-12 months). Patient-level cost data began accruing from the first paid claim and continued accruing until the censoring date. RESULTS: A total of 2,199 patients with mPDA initiated first-line AG (n = 1,352) or FFX (n = 847). Compared with AG initiators, FFX patients were younger (mean age 59 vs. 63 years) and had better baseline health status, with fewer having diabetes (43% vs. 57%) or coronary artery disease (12% vs. 22%). Median follow-up was 5.4 and 7.2 months for AG and FFX, respectively. Median first-line treatment duration was 2.1 months with AG and 2.3 months with FFX. Six months following first-line treatment initiation, total cumulative health care costs (median) were $85,714 (95% CI = $79,683-$91,788) and $114,116 (95% CI = $105,816-$119,591) for AG and FFX initiators, respectively. Outpatient services contributed the largest fractional cost for both groups. CONCLUSIONS: Total health care costs for patients with mPDA who initiated FFX or AG are driven mostly by outpatient rather than inpatient costs. Further research, using comparative methodology, is warranted to fully understand cost drivers and whether higher costs for FFX patients relate primarily to use of FFX or higher underlying use of outpatient care among FFX patients. DISCLOSURES: This study was funded by Halozyme Therapeutics. Oestreicher and Yeganegi were employees of Halozyme Therapeutics at the time of the study and were involved in study design, data interpretation, and the decision to submit the data for publication. Bullock reports advisory board fees from Eisai, Exelixis, Bayer, and Taiho and consulting fees from Halozyme Therapeutics, outside the submitted work. Rowan reports consulting fees from Halozyme Therapeutics, during the conduct of the study. Chiorean reports grants and consulting fees from Celgene and Halozyme Therapeutics; grants from Lilly, Stemline, Ignyta, Roche, Merck, Boehringer-Ingelheim, Bristol Meyer Squibb, Incyte, Macrogenics, Rafael, and AADi; and consulting fees from Astra Zeneca, Array, Eisai, Ipsen, Five Prime Therapeutics, Seattle Genetics, Vicus, and Legend, outside the submitted work.

Assessment of Duration and Effects of 3 vs 6 Months of Adjuvant Chemotherapy in High-Risk Stage II Colorectal Cancer: A Subgroup Analysis of the TOSCA Randomized Clinical Trial.

Importance: The addition of oxaliplatin to the standard 6-month fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer has been reported to reduce the risk of relapse although it does not increase survival. The Three or Six Colon Adjuvant (TOSCA) trial compared 3 months with 6 months of adjuvant fluoropyrimidine and oxaliplatin-based chemotherapy in patients with stage III colon cancer. The utility remains unknown. Objective: To assess the noninferiority and toxic effects of 3 vs 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) adjunct chemotherapy among patients with high-risk stage II resected colorectal cancer enrolled in the TOSCA trial. Design, Setting, and Participants: The TOSCA study was a noninferiority phase 3 randomized clinical trial conducted from June 2007 to March 2013 in 130 Italian centers. Included patients had resected colorectal cancer located 12 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. In this preplanned study assessing the per-protocol population, 5-year relapse-free survival was evaluated in 1254 patients with high-risk stage II resected colorectal cancer who had received adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Interventions: Patients were originally randomized (1:1) in the TOSCA trial to receive 3 months (experimental group) or 6 months (control) of standard doses of FOLFOX or CAPOX at the discretion of the treating physician. Main Outcome and Measures: A hazard ratio of at least 1.2 between the 3-month and 6-month chemotherapy groups was set to reject the null hypothesis of noninferiority. Results: Overall, 1254 patients (mean [SD] age, 62.4 [9.8] years; 565 women [45.1%]) with clinical high-risk stage II resected colorectal cancer were analyzed at a median follow-up of 62 months (interquartile range, 53-71) months. Of them, 301 patients (24.0%) had pT4N0M0 tumors, and the remaining 953 patients (76.0%) had high-risk pT3N0M0 tumors; 776 patients (61.9%) received FOLFOX and 478 (38.1%) received CAPOX. The 5-year relapse-free survival was 82.2% for the 3-month arm and 88.2% for the 6-month arm, with an estimated hazard ratio of 1.41 (95% CI, 1.05-1.89; P = .86 for noninferiority). For CAPOX, the 5-year relapse-free survival was similar in the 2 arms (difference, 0.76% favoring the 6-month arm; 95% CI, -6.28% to 7.80%), whereas for FOLFOX, the difference was pronounced: 8.56% in favor of the longer-duration arm (95% CI, 3.45%-13.67%). Nevertheless, the test for an interaction between duration and regimen was not statistically significant. Neurotoxicity was approximately 5 times lower in the shorter duration arm than in the longer duration arm. Conclusions and Relevance: In the 3-month arm, the treatment was significantly less toxic than in the 6-month arm. Noninferiority was not shown for 5-year relapse-free survival. However, a possible regimen effect was observed, suggesting that either 3 months of CAPOX or 6 months of FOLFOX therapy can be used whenever an oxaliplatin doublet is indicated for treatment of patients with stage II colorectal cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT0064660.

Assessment of Oxaliplatin-induced Chronic Neuropathy and Anticancer Efficacy Through Pharmacokinetic and Toxicodynamic Evaluation of a Rat Model of Colorectal Cancer.

BACKGROUND/AIM: Oxaliplatin-induced chronic neuropathy is a prominent factor for dose reduction and not completing all cycles of chemotherapy for patients with colorectal cancer (CRC). The aim of the study was to investigate the pharmacokinetics and toxicodynamics of oxaliplatin-induced chronic neuropathy in CRC rats to ensure effective management. MATERIALS AND METHODS: A rat model of CRC was developed using 1,2-Dimethylhydrazine and dextran sulfate. Oxaliplatin (L-OHP) was administered intravenously to CRC rats every week. The pharmacokinetic profiles and tumor distribution of L-OHP and chronic neuropathies were investigated for over four weeks. RESULTS: The mean values of the area under the concentration-time curve for L-OHP showed a dose-dependent increase. Chronic neuropathy occurred from Day 14 in the 8 mg/kg group and Day 19 in the 3 and 5 mg/kg groups. CONCLUSION: These results provide preliminary information for the development of a pharmacokinetic and toxicodynamic model of L-OHP for CRC therapy cycles.

Effectiveness assessment of riluzole in the prevention of oxaliplatin-induced peripheral neuropathy: RILUZOX-01: protocol of a randomised, parallel, controlled, double-blind and multicentre study by the UNICANCER-AFSOS Supportive Care intergroup.

INTRODUCTION: Most patients (>70%) experience acute neuropathic symptoms shortly after oxaliplatin infusions. These symptoms are not always resolved between infusions. Overall, 30%-50% of patients suffer from chronic oxaliplatin-induced peripheral neuropathy (OIPN). This cumulative and dose-dependent sensory neuropathy limits compliance or results in oxaliplatin-based chemotherapies to be substituted with less neurotoxic agents. These treatment changes impair clinical outcomes, and may be associated with comorbidities, such as distress, depression and anxiety. Currently, no drug used to prevent or treat OIPN is sufficiently effective to be used routinely in clinical practice. There is, thus, an unmet therapeutic need to reduce the intensity of and/or prevent OIPN. We hypothesised that riluzole would be an excellent candidate to address this public health issue. Riluzole is approved for treating amyotrophic lateral sclerosis. In animals, there is a beneficial effect on sensorimotor and pain disorders, as well as related comorbidities, after repeated administration of oxaliplatin. In humans, riluzole has shown neuroprotective, anxiolytic and antidepressive effects. METHODS AND ANALYSIS: RILUZOX-01 trial was designed as a randomised, controlled, double-blind study to evaluate the efficacy of riluzole to prevent OIPN. Patients with colorectal cancer and initiating adjuvant oxaliplatin-based chemotherapy are eligible. Patients (n=210) will be randomly assigned to either riluzole or placebo, concomitantly with chemotherapy. The primary endpoint is the change in OIPN intensity, assessed by the sensory scale of the QLQ-CIPN20, after six 2-week cycles of chemotherapy. Secondary endpoints include incidence and severity of neuropathy, grade of sensory neuropathy, intensity and features of neuropathic pain, health-related quality of life, disease-free survival, overall survival and safety. ETHICS AND DESSIMINATION: The study was approved by a French ethics committee (ref:39/18_1, 'Comité de Protection des Personnes' Ouest-IV, France) and plans to start enroling patients in September 2019. The trial is registered in EudraCT and clinicaltrials.gov. TRIAL REGISTRATION NUMBER: N°2017-002320-25; NCT03722680.

Cost-effectiveness analysis of long-course oxaliplatin and bolus of fluorouracil based preoperative chemoradiotherapy vs. 5x5Gy radiation plus FOLFOX4 for locally advanced resectable rectal cancer.

PURPOSE: To evaluate the cost-effectiveness of preoperative short-course radiotherapy (SCRT, 5 × 5 Gy) plus FOLFOX4 versus long-course oxaliplatin and bolus of fluorouracil based preoperative long-course chemoradiotherapy (LCCRT, 50.4 Gy in 28 fractions) in the management of cT4 or advanced cT3 rectal cancer (RC), both of which have been reported to achieve similar clinical effect in the NCT00833131 trial. MATERIALS AND METHODS: A Markov decision-analytic model compared SCRT plus chemotherapy and LCCRT, by simulating three health states (disease-free survival (DFS), progressive disease (PD) and death). The primary outcomes were quality-adjusted life months (QALMs), costs, and incremental cost-effectiveness ratios (ICERs). Transition probabilities were based on the NCT00833131 trial. The costs were calculated from a Chinese payers' perspective. Strategies were evaluated with a willingness-to-pay (WTP) threshold of $2370.47 (3 × GDP) per QALM gained. Sensitivity analysis was performed to model uncertainty in these parameters. RESULTS: The overall costs for SCRT plus chemotherapy and LCCRT were $78,937 and $38,140 with effectiveness of 29.92 QALMs and 22.99 QALMs, respectively. SCRT plus chemotherapy increased costs and QALM by $40,797.34 and 6.93 compared to LCCRT, resulting in an ICER of $5884.56/QALM gained. In the DFS state, the whole cost for SCRT plus chemotherapy and LCCRT were $11,490.03 and $10,794.06 with an effectiveness of 21.70 QALMs and 19.65 QALMs, respectively. SCRT plus chemotherapy increased cost and QALM by $695.97 and 2.05 compared to LCCRT, resulting in a ICER of $339.50/QALM gained, which below the WTP. The utility associated with the DFS state was the most influential factor on the cost-effectiveness of SCRT plus chemotherapy. When the cost of PD state below $1920, the ICER of SCRT compared with LCCRT below the WTP. CONCLUSION: Compared with LCCRT, SCRT plus chemotherapy is a more cost-effective strategy for locally advanced resectable RC in the DFS state as well as in the all states when the cost of PD state below $1920.

Comparison of Medicare Claims-based Proxy Measures of Poor Function and Associations With Treatment Receipt and Mortality in Older Colon Cancer Patients.

BACKGROUND: Multiple claims-based proxy measures of poor function have been developed to address confounding in observational studies of drug effects in older adults. We evaluated agreement between these measures and their associations with treatment receipt and mortality in a cohort of older colon cancer patients. METHODS: Medicare beneficiaries age 66+ diagnosed with stage II-III colon cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare database (2004-2011). Poor function was operationalized by: (1) summing the total poor function indicators for each model; and (2) estimating predicted probabilities of poor function at diagnosis. Agreement was evaluated using Fleiss' κ and Spearman's correlation. Associations between proxy measures and: (1) laparoscopic versus open surgery; (2) chemotherapy versus none; (3) 5-fluorouracil (5FU)+oxaliplatin (FOLFOX) versus 5FU monotherapy; and (4) 1-year mortality were estimated using log-binomial regression, controlling for age, sex, stage, and comorbidity. Survival estimates were stratified by functional group, age, and comorbidity. RESULTS: Among 29,687 eligible colon cancer patients, 67% were 75+ years and 45% had stage III disease. Concordance across the poor function indicator counts was moderate (κ: 0.64) and correlation of predicted probability measures varied (ρ: 0.21-0.74). Worse function was associated with lower chemotherapy and FOLFOX receipt, and higher 1-year mortality. Within age and comorbidity strata, poor function remained associated with mortality. CONCLUSIONS: While agreement varied across the claims-based proxy measures, each demonstrated anticipated associations with treatment receipt and mortality independent of comorbidity. Claims-based comparative effectiveness studies in older populations should consider applying one of these models to improve confounding control.

Eficacia y seguridad de cetuximab en pacientes adultos con cáncer de colon metastásico e irresecable, tumor primario de localización izquierda y genes kras/nras no mutados, sin tratamiento previo / Efficacy and safety of cetuximab in adult patients with metastatic and unresectable colon cancer, primary tumor of left location and non-mutated kras / nras genes, without prior treatment

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de cetuximab asociado a FOLFOX en comparación con únicamente FOLFOX, en pacientes adultos con cáncer de colon metastásico e irresecable, con tumor primario de localización izquierda y genes KRAS/NRAS no mutados, sin tratamiento previo. El cáncer colorrectal (CCR) es el tercer cáncer más frecuente y el segundo cáncer más mortal en todo el mundo, representado alrededor de 10.2 % de la totalidad de diagnósticos de cáncer y 9.2 % de la totalidad de muertes debido a cáncer, con una tendencia ascendente en su incidencia acumulada y mortalidad. A menudo la enfermedad se diagnostica tardíamente cuando se ha propagado a distancia y no es quirúrgicamente resecable. En este contexto, los pacientes tienen como opción terapéutica de primera línea a la quimioterapia a base de FOLFOX (ácido folínico, fluoracilo y oxaliplatino), FOLFIRI (ácido folínico, fluoracilo e irinotecan), FOLFIRINOX (ácido folínico, fluoracilo, irinotecán y oxaliplatino) o XELOX (capecitabina y oxaliplatino); todos los cuales se encuentran disponibles en el Petitorio Farmacológico de EsSalud. TECNOLOGÍA SANITARIA DE INTERÉS: Cetuximab. El fármaco cetuximab (Erbitux® - Merck Peruana S.A) es un anticuerpo monoclonal IgG1 quimérico recombinante producido en una línea celular de mamíferos (Sp2/0). Se une al EGFR e inhibe competitivamente la unión entre el factor de crecimiento epidérmico y otros ligandos. La unión de cetuximab al EGFR resulta en la inhibición del crecimiento celular y la inducción de apoptosis. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura, de la cual se obtuvo cinco guías de práctica clínica (GPC), tres evaluaciones de tecnologías sanitaria (ETS) y un ensayo clínico aleatorizado (ECA) de fase III, el estudio TAILOR, que responde directamente a la pregunta PICO del presente dictamen en base a los resultados de un análisis post hoc exploratorio (subgrupo de pacientes con tumores primarios de localización izquierda). RESULTADOS: En los documentos de GPC consultados, fue común la ausencia de recomendaciones específicas del tratamiento del CCRm respecto a la localización izquierda o derecha del tumor primario. Las GPC elaboradas por National Institute for Health and Care Excellence (NICE), Japanese Society for Cancer of the Colon and Rectum (JSCCR), el Scottish Intercollegiate Guidelines Network (SIGN) y la European Society for Medical Oncology (ESMO) recomendaron el uso de cetuximab más FOLFOX en pacientes con CCRm e irresecable y genes KRAS/NRAS no mutados, no tratados previamente, independientemente de la localización del tumor primario. Sin embargo, la guía de la National Comprensive Cancer Network (NCCN) limitó su uso a la presencia de tumores primarios de localización izquierda. Esta recomendación se basó en los resultados del estudio TAILOR, que fue evaluado en el presente dictamen. Por otro lado, con excepción de la guía de la JSCCR, las guías evaluadas en el presente dictamen también recomendaron el esquema FOLFOX sin la adición de cetuximab como una alternativa de tratamiento para nuestra población de interés, con un nivel de evidencia o categoría de recomendación similar o superior que la valorada para cetuximab más FOLFOX. CONCLUSIONES: El presente documento tuvo como objetivo evaluar la eficacia y seguridad de cetuximab más FOLFOX vs solo FOLFOX, en pacientes adultos con cáncer de colon metastásico e irresecable, tumor primario de localización izquierda y genes KRAS/NRAS no mutados, sin tratamiento previo. Nuestra revisión de la evidencia disponible hasta marzo del 2019, permitió identificar al estudio TAILOR, como la principal fuente de información para la evaluación de los efectos de cetuximab más FOLFOX en la población de interés. El estudio TAILOR es un ECA de fase III, multicéntrico y de etiqueta abierta, que evaluó el uso cetuximab más FOLFOX-4 comparado con solo FOLFOX-4, para el tratamiento de primera línea en pacientes adultos con CCRm e irresecable y genes KRAS/NRAS no mutados. Como parte de un análisis post hoc exploratorio, el estudio evaluó la SG en el subgrupo de pacientes con tumores primarios de localización izquierda, que es nuestra población de interés. En este subgrupo de pacientes, se reportan diferencias estadísticamente significativas en la SG a favor del uso de cetuximab más FOLFOX-4 en comparación con el uso de solo FOLFOX-4. Sin embargo, la prueba de interacción estadística, no identificó a la presencia de tumores primarios de localización izquierda como una variable que modifique el efecto de cetuximab más FOLFOX en la población general del estudio; por lo que el reporte de resultados según la ubicación del tumor primario solo tuvo un carácter exploratorio y no debería considerarse como evidencia concluyente en la evaluación de la eficacia de la tecnología de interés. Asimismo, es importante resaltar que los análisis de subgrupos no preespecificados aumentan la probabilidad de detectar diferencias estadísticamente significativas cuando en realidad no las hay, esto debido a errores aleatorios que surgen de las múltiples comparaciones exploratorias. En ese sentido, se debe dejar en claro que, los análisis de subgrupos post hoc, solo son útiles para generar hipótesis que deben ser evaluadas en futuros ECA correctamente diseñados. Otras limitaciones que afectaron la validez del estudio TAILOR fueron las siguientes: i) el evaluar solo pacientes de ciudadanía china, lo que limita la extrapolación de sus hallazgos a otras poblaciones; y ii) el diseño fue de etiqueta abierta, lo que incrementa el riesgo de sesgo de detección (por parte del investigador) y/o desempeño (por parte del paciente) y que puede afectar los hallazgos del estudio. Con respecto a la evaluación de la seguridad, el estudio TAILOR reportó una mayor incidencia de EA serios y EA de grado 3 o superior, y una mayor discontinuación de la quimioterapia debido a EA con cetuximab más FOLFOX comparado con solo FOLFOX. En ese sentido, existe una gran preocupación en lo que respecta la seguridad de cetuximab añadido a FOLFOX lo que, sumado a la incertidumbre sobre el beneficio clínico que aporta este régimen, no permite identificar una ganancia neta en el balance riesgo beneficio con el uso de cetuximab más FOLFOX en comparación con solo FOLFOX, en la población de interés de la pregunta PICO. Durante la elaboración de este dictamen preliminar, no se encontró evidencia sobre la calidad de vida de los pacientes que recibieron cetuximab asociado a FOLFOX como tratamiento de primera línea en la población de interés. Cabe mencionar que cetuximab es una tecnología sanitaria de alto costo, cuya implementación supondría un incremento en los costos anuales de aproximadamente S/. 290,296.00 por paciente (considerando solo la adquisición del medicamento), la cual, en base a la incertidumbre en relación al beneficio neto ganado con esta tecnología, no es posible sustentar técnicamente como una inversión costo-oportuna para un sistema de salud público, como es el caso de EsSalud. Por lo expuesto, el IETSI no aprueba el uso de cetuximab añadido a FOLFOX como tratamiento de primera línea de pacientes adultos con cáncer de colon metastásico e irresecable, tumor primario de localización izquierda y genes KRAS/NRAS no mutados.

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.

Economic Evaluation for the UK of Systemic Chemotherapies as First-Line Treatment of Metastatic Pancreatic Cancer.

BACKGROUND: Gemcitabine (GEM), oxaliplatin plus GEM (OX + GEM), cisplatin plus GEM (CIS + GEM), capecitabine plus GEM (CAP + GEM), FOLFIRINOX (FFX), and nab-paclitaxel plus GEM (NAB-P + GEM) are the most commonly used regimens as first-line treatment of metastatic pancreatic cancer (MPC) in the UK. Independent economic evaluation of these regimens simultaneously has not been conducted for the UK. OBJECTIVE: Using data from a network meta-analysis as efficacy measures, we estimated the cost effectiveness and cost utility of these regimens for the UK. METHODS: A three-state Markov model (progression-free, progressed-disease, and death) simulating the total costs and health outcomes (quality-adjusted life-years [QALYs] gained and life-years [LYs]) was developed to estimate the incremental cost-utility (ICUR) and incremental cost-effectiveness ratios (ICER) for patients with MPC, from the payer perspective. The model was specified to calculate total costs in 2017 British pounds (GBP, £). All values were discounted at 3.5% per year over a full lifetime horizon. One-way sensitivity and probabilistic sensitivity analyses were conducted to assess the impact of parameter uncertainty on the results. RESULTS: FFX was the most effective regimen, NAB-P + GEM was the most costly regimen, and GEM was the least costly and least effective regimen. OX + GEM, CIS + GEM, and NAB-P + GEM were dominated by CAP + GEM and FFX. Compared with GEM, the ICUR for CAP + GEM and FFX was £28,066 and £33,020/QALY gained, respectively; compared with GEM, the ICER for CAP + GEM and FFX was £17,437 and £22,291/LY gained, respectively; and compared with CAP + GEM, the ICUR and ICER for FFX were £34,947/QALY gained and 24,414/LY gained, respectively. CONCLUSIONS: At a threshold value of £30,000/QALY, CAP + GEM was found to be the only cost-effective regimen in the management of MPC in the UK.

Cost-effectiveness analysis of capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer.

BACKGROUND: There is no single standard chemotherapy regimen for elderly patients with advanced gastric cancer (AGC). A phase III trial has confirmed that both capecitabine monotherapy and capecitabine plus oxaliplatin are well tolerated for elderly patients with AGC, but their economic influence in China is unknown. OBJECTIVE: The purpose of this cost-effectiveness analysis was to estimate the effects of capecitabine monotherapy and capecitabine plus oxaliplatin in elderly patients with AGC on health and economic outcomes in China. METHODS: We created a Markov model based on data from a Korean clinical phase III trial to analyze the cost-effectiveness of the treatment of elderly patients in the capecitabine monotherapy (X) group and capecitabine plus oxaliplatin (XELOX) group. The costs were obtained from published reports and the local health system. The utilities were assumed on the basis of the published literature. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. One-way and probabilistic sensitivity analyses (Monte Carlo simulations) were performed. RESULTS: In the cost-effectiveness analysis, X had a lower total cost ($45,731.68) and cost-effectiveness ratio ($65,918.93/QALY). The one-way sensitivity analysis suggested that the most influential parameter was the risk of requiring second-line chemotherapy in XELOX group. The probabilistic sensitivity analysis predicted that the X regimen was cost-effective 100% of the time, given a willingness-to-pay threshold of $26,598. CONCLUSIONS: Our findings show that the XELOX regimen is less cost-effective compared to the X regimen for elderly patients with AGC in China from a Chinese healthcare perspective.