Assessment of efficacy of postinfusion tubing flushing in reducing risk of cytotoxic contamination.

PURPOSE: Infusion of cytotoxic drugs carries the risk of occupational exposure of healthcare workers. Since disconnecting an infusion line is a source of contamination, flushing of tubing after infusion of cytotoxic agents is recommended, but the optimal volume of rinsing solution is unknown. The objective of this study was to assess whether postinfusion line flushing completely eliminates cytotoxics. METHODS: Infusions were simulated with 3 cytotoxics (gemcitabine, cytarabine, and paclitaxel) diluted in 5% dextrose injection or 0.9% sodium chloride injection in 250-mL infusion bags. Infusion lines were flushed using 5% dextrose injection or 0.9% sodium chloride solution at 2 different flow rates. The remaining concentration of cytotoxics in the infusion line was measured by a validated high-performance liquid chromatography (HPLC) method after passage of every 10 mL of flushing volume until a total of 100 mL had been flushed through. RESULTS: All cytotoxics remained detectable even after line flushing with 80 mL of flushing solution (a volume 3-fold greater than the dead space volume within the infusion set). Gemcitabine and cytarabine were still quantifiable via HPLC even after flushing with 100 mL of solution. Efficacy of flushing was influenced by the lipophilicity of drugs but not by either the flushing solvent used or the flushing flow rate. After 2-fold dead space volume flushing, the estimated amount of drug remaining in the infusion set was within 0.19% to 0.56% of the prescribed dose for all 3 cytotoxics evaluated. CONCLUSION: Complete elimination of cytotoxics from an infusion line is an unrealistic objective. Two-fold dead space volume flushing could be considered optimal in terms of administered dose but not from an environmental contamination point of view. Even when flushed, the infusion set should still be considered a source of cytotoxic contamination.

Time-Series Modeling and Simulation for Comparative Cost-Effective Analysis in Cancer Chemotherapy: An Application to Platinum-Based Regimens for Advanced Non-small Cell Lung Cancer.

The purpose of this study was to propose a time-series modeling and simulation (M&S) strategy for probabilistic cost-effective analysis in cancer chemotherapy using a Monte-Carlo method based on data available from the literature. The simulation included the cost for chemotherapy, for pharmaceutical care for adverse events (AEs) and other medical costs. As an application example, we describe the analysis for the comparison of four regimens, cisplatin plus irinotecan, carboplatin plus paclitaxel, cisplatin plus gemcitabine (GP), and cisplatin plus vinorelbine, for advanced non-small cell lung cancer. The factors, drug efficacy explained by overall survival or time to treatment failure, frequency and severity of AEs, utility value of AEs to determine QOL, the drugs' and other medical costs in Japan, were included in the model. The simulation was performed and quality adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER) were calculated. An index, percentage of superiority (%SUP) which is the rate of the increased cost vs. QALY-gained plots within the area of positive QALY-gained and also below some threshold values of the ICER, was calculated as functions of threshold values of the ICER. An M&S process was developed, and for the simulation example, the GP regimen was the most cost-effective, in case of threshold values of the ICER=$70000/year, the %SUP for the GP are more than 50%. We developed an M&S process for probabilistic cost-effective analysis, this method would be useful for decision-making in choosing a cancer chemotherapy regimen in terms of pharmacoeconomic.

Economic evaluation for the US of nab-paclitaxel plus gemcitabine versus FOLFIRINOX versus gemcitabine in the treatment of metastatic pancreas cancer.

BACKGROUND: Nab-paclitaxel plus gemcitabine (NAB-P + GEM) and FOLFIRINOX have shown superior efficacy over gemcitabine (GEM) in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDA). Although the incremental clinical benefits are modest, both treatments represent significant advances in the treatment of a high-mortality cancer. In this independent economic evaluation for the US, the aim was to estimate the comparative cost-utility and cost-effectiveness of these three regimens from the payer perspective. METHODS: In the absence of a direct treatment comparison in a single clinical trial, the Bucher indirect comparison method was used to estimate the comparative efficacy of each regimen. A Markov model evaluated life years (LY) and quality-adjusted life years (QALY) gained with NAB-P + GEM and FOLFIRINOX over GEM, expressed as incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR). All costs and outcomes were discounted at 3%/year. The impact of parameter uncertainty on the model was assessed by probabilistic sensitivity analyses. RESULTS: NAB-P + GEM was associated with differentials of +0.180 LY and +0.127 QALY gained over GEM at an incremental total cost of $25,965; yielding an ICER of $144,096/LY and ICUR of $204,369/QALY gained. FOLFIRINOX was associated with differentials of +0.368 LY and +0.249 QALY gained over GEM at an incremental total cost of $93,045; yielding an ICER of $253,162/LY and ICUR of $372,813/QALY gained. In indirect comparison, the overall survival hazard ratio (OS HR) for NAB-P + GEM vs FOLFIRINOX was 0.79 (95%CI = 0.59-1.05), indicating no superiority in OS of either regimen. FOLFIRINOX had an ICER of $358,067/LY and an ICUR of $547,480/QALY gained over NAB-P + GEM. Tornado diagrams identified variation in the OS HR, but no other parameters, to impact the NAB-P + GEM and FOLFIRINOX ICURs. CONCLUSIONS: In the absence of a statistically significant difference in OS between NAB-P + GEM and FOLFIRINOX, this US analysis indicates that the greater economic benefit in terms of cost-savings and incremental cost-effectiveness and cost-utility ratios favors NAB-P + GEM over FOLFIRINOX.

An assessment of the benefit-risk balance of FOLFIRINOX in metastatic pancreatic adenocarcinoma.

BACKGROUND: We sought to assess the benefit-risk balance of FOLFIRINOX versus gemcitabine in patients with metastatic pancreatic adenocarcinoma. METHODS: We used generalized pairwise comparisons. This statistical method permits the simultaneous analysis of several prioritized outcome measures. The first priority outcome was survival time (OS). Differences in OS that exceeded two months were considered clinically relevant. The second priority outcome was toxicity. The overall treatment effect was quantified using the net chance of a better outcome, which can be interpreted as the net probability for a random patient treated in the FOLFIRINOX group to have a better overall outcome than a random patient in the gemcitabine group. RESULTS: In this trial 342 patients received either FOLFIRINOX or gemcitabine. The net chance of a better outcome favored strongly and significantly the FOLFIRINOX group (24.7; P<.001), suggesting a favorable benefit-risk balance of FOLFIRINOX versus gemcitabine. The positive benefit-risk balance of FOLFIRINOX was observed throughout all sensitivity analyses. CONCLUSIONS: Generalized pairwise comparisons are useful to perform a quantitative assessment of the benefit-risk balance of new treatments. It provides a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. Overall the benefit-risk balance of FOLFIRINOX was strongly positive.

Current status of systemic chemotherapy for octogenarians with advanced urothelial cancer in Japan: a Japanese multi-institutional study (CURE study).

BACKGROUND: The standard regimen of systemic chemotherapy for patients with advanced urothelial cancer (UC) changed from methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) to gemcitabine and cisplatin (GC) in 2008 when the use of gemcitabine for UC began to be reimbursed by public health insurance in Japan. We examined its influence on the chemotherapy trend in elderly patients aged ≥80 years. METHODS: Among 345 patients included in our previous multicenter retrospective cohort study (chemotherapy for urothelial carcinoma: renal function and efficacy study; CURE study), the outcome of 30 patients aged ≥80 years was reviewed before and after 2008 and compared with 315 young patients. RESULTS: There were only 7 (4.6 %) elderly individuals among all registered patients before 2008, whereas the number increased to 23 (12 %) after 2008. Before 2008, only one elderly patient received MVAC, while GC (whose rate was similar to the rate in young patients) was administered to 13 patients (56.5 %) after 2008. The chemotherapeutic effect and overall survival (OS) rate was not significantly different between young and elderly patients. In the elderly treated with the GC regimen, the renal impairment rate after the first cycle was significantly higher, and the presence of distant metastases and renal impairment were independent prognostic factors in a multivariate analysis. CONCLUSION: Since GC was approved as the standard regimen for first-line chemotherapy in UC, selected elderly patients have been able to safely receive systemic chemotherapy like young patients. The clinical response rate and OS rate were similar to the young, but we need to monitor changes in renal function more closely in the elderly treated with GC.

Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: results from the OMEGA study of the Dutch breast cancer trialists' group.

AIM: To evaluate the association between baseline comprehensive geriatric assessment (CGA) or the Groningen Frailty Indicator (GFI) and toxicity in elderly metastatic breast cancer (MBC) patients treated with first-line palliative chemotherapy. PATIENTS AND METHODS: MBC patients (≥65 years) were randomized between pegylated liposomal doxorubicine or capecitabine. CGA included instrumental activities of daily living (IADL), cognition using the mini-mental state examination (MMSE), mood using the geriatric depression scale (GDS), comorbidity using the Charlson index, polypharmacy and nutritional status using the body mass index. Frailty on CGA was defined as one or more of the following: IADL ≤ 13, MMSE ≤ 23, GDS ≥ 5, BMI ≤ 20, ≥5 medications or Charlson ≥2. The cut-off for frailty on the GFI was ≥4. RESULTS: Of the randomized 78 patients (median age 75.5 years, range 65.8-86.8 years), 73 were evaluable for CGA; 52 (71%) had one or more geriatric conditions. Grade 3-4 chemotherapy-related toxicity was experienced by 19% of patients without geriatric conditions compared to 56% of patients with two geriatric conditions and 80% of those with three or more (p = 0.002). Polypharmacy was the only individual factor significantly associated with toxicity (p = 0.001). GFI had a sensitivity of 69% and a specificity of 76% for frailty on CGA, and was not significantly associated with survival or toxicity. CONCLUSION: In this study of elderly patients with MBC, the number of geriatric conditions correlated with grade 3-4 chemotherapy-related toxicity. Therefore, in elderly patients for whom chemotherapy is being considered, a CGA could be a useful addition to the decision-making process.

Assessment and management of renal impairment in chemotherapy for urogenital cancer.

The method of diagnosing chronic kidney disease by simple estimated glomerular filtration rate equations has demonstrated a high prevalence of chronic kidney disease among the genitourinary cancer patients. Approximately 30-50% of urothelial cancer patients have Grade 3 chronic kidney disease before chemotherapy, and the rate increases to around 80% in upper urinary tract cancer patients who have undergone radical surgery. Several gold-standard treatments, including cisplatin for urothelial/testicular tumors and anti-vascular endothelial growth factor therapy for kidney cancers, are known to be associated with the development of renal impairment. However, which renal function assessments are best to select a chemotherapy regimen remain unknown. Most testicular tumor patients are cured by intensive combined chemotherapy with cisplatin, but chemotherapy can induce chronic kidney disease in testicular cancer survivors. The prevalence of Stage 3 chronic kidney disease among the testicular cancer survivors is between 10 and 20%. Thus, the estimated glomerular filtration rate assessment is a useful tool for monitoring the development of chronic kidney disease among the cancer survivors, and assessment of renal function is mandatory before the treatment of these genitourinary cancer patients.

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.

[Assessment of hand-foot syndrome in cancer patients treated with capecitabine-containing chemotherapy].

Capecitabine is one of the most effective oral chemotherapeutic drugs for advanced or recurrent colorectal cancer and gastric cancer. Capecitabine-containing chemotherapy is recommended as a first-line option for gastrointestinal tract cancer. The incidence of hand-foot syndrome (HFS), an adverse event of chemotherapy with capecitabine, is high. Moreover, once the symptoms of HFS are identified, they can significantly impair the quality of life (QOL) of patients. HFS should be managed by dose interruption and, if necessary, by dose reduction. Pharmacists and oncology nurses play an increasingly important role in the early identification and prevention of HFS through patient education and close clinical assessment. The aim of this study was to evaluate the efficacy of support tools for the early identification, prevention, and management of HFS and to assess the effectiveness of "patient self-check sheets". The patient was detected as having HFS of mild severity and had used a moisturizer at the time of initiation of therapy. Maintaining moisture retention is important in the management of HFS. The ambulatory team plays a key role by using self-check sheets to educate patients on how to recognize HFS, when to interrupt treatment, and how to adjust the dose so as to maintain effective therapy with capecitabine. For the continuation and completion of treatment and for maintaining an improved QOL in the home environment, supportive measures for adverse effects such as HFS and an ambulatory team are indispensable.

[Assessment of hand-foot syndrome in cancer outpatients undergoing chemotherapy].

Capecitabine, an oral prodrug of 5 -fluorouracil, is a promising treatment for colorectal, breast, and gastric cancers, but often causes hand-foot syndrome(HFS), which is the most common dose-limiting toxicity. The aim of this study was to evaluate of the efficacy of the pharmacist in providing support at ambulatory therapy centers, especially for HFS. The HFS is a higher-incidence adverse event that may develop during chemotherapy with capecitabine. Once developed, the symptoms significantly impair quality of life(QOL), leading to a reduction in the dosage or discontinuation of the treatment. Patient symptoms may therefore increase in severity. This study was performed to analyze the treatment adherence and adverse events resulting from capecitabine therapy provided by pharmacists to cancer outpatients. All patients were prescribed vitamin B6(pyridoxine), which can help to reduce or prevent HFS. A lesser or milder extent of HFS was detected in patients who had used a moisturizer at the same time as the introduction of capecitabine therapy. Adherence to this approach will benefit the patients' selfcare in maintaining moisture retention, which is an important countermeasure for HFS. Additionally, early introduction of effective countermeasures for skin care, dose reduction, and rest periods is important for HFS management; in addition, team care support is dispensable. Our support system may be useful for management strategies for HFS. We suggest that improved quality of lif e is needed in cancer outpatients being treated with chemotherapy.

[Analysis of adherence and efficiency when replacing an antiretroviral therapy with efavirenz-emtricitabine-tenofovir in a single daily dose]. / Análisis del cambio en la adherencia y eficiencia del tratamiento antirretroviral con el uso de efavirenz-emtricitabina-tenofovir en dosis única diaria.

OBJECTIVE: To analyse whether the change of antiretroviral therapy to efavirenz/emtricitabine/tenofovir in a single daily dose (EETu) increases adherence and maintains effectiveness, and establish the cost increase caused by the change. METHODS: An observational, retrospective, and intra-subject study, performed in the outpatient dispensing unit. The study period was 1 year (6 months before and 6 months after the change). Computer dispensing records and days of hospitalisation during the study period were reviewed, and the difference in treatment adherence calculated. To determine the effectiveness of treatment, viral load and CD4 lymphocytes data before and after the change were reviewed. The cost before and after treatment for each patient was determined, and therefore the annual cost increase and the incremental cost per patient. RESULTS: The study included 127 patients. The difference in adherence was 0.6%. The percentage of poor adherence was 35.4% and 40.9% before and after the treatment change, respectively. The levels of CD4 lymphocytes and viral load did not change significantly with treatment. The economic analysis revealed an annual increase of 25,374.60 and €199.80 per patient. CONCLUSIONS: The use of EETu did not improve the control of HIV infection in terms of effectiveness and adherence, and resulted in increased economic costs. Therefore, its choice as antiretroviral treatment will have to be based on criteria other than those described above.

What primary care providers need to know about preexposure prophylaxis for HIV prevention: a narrative review.

As HIV prevalence climbs globally, including more than 50 000 new infections per year in the United States, we need more effective HIV prevention strategies. The use of antiretrovirals for preexposure prophylaxis (PrEP) among high-risk persons without HIV is emerging as one such strategy. Randomized, controlled trials have demonstrated that once-daily oral PrEP decreased HIV incidence among at-risk men who have sex with men and African heterosexuals, including serodiscordant couples. An additional randomized, controlled trial of a topical pericoital antiretroviral microbicide gel decreased HIV incidence among at-risk heterosexual South African women. Two other studies in African women did not demonstrate the efficacy of oral or topical PrEP, raising concerns about adherence patterns and efficacy in this population. The U.S. Food and Drug Administration (FDA) Antiviral Drugs Advisory Committee reviewed these studies and additional data in May 2012 and voted to advise the approval of oral tenofovir-emtricitabine for PrEP in high-risk populations. On 16 July 2012, the FDA recommended that this combination medication be approved for use as PrEP in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic.

Assessment of gemcitabine, cisplatin and methylprednisolone (GEM-P) combination treatment for non-Hodgkin T cell lymphoma.

T cell lymphoma is rare with few dedicated studies and no consensus regarding optimal treatment. We undertook a retrospective hospital review to assess the efficacy of gemcitabine, cisplatin and methylprednisolone (GEM-P) combination therapy. Twenty-nine patients were followed up for a median duration of 28 months. Twenty-three patients received standard GEM-P. Due to hearing impairment, 3 patients had cisplatin substituted with carboplatin and 1 with oxaliplatin. In 2 cases, rituximab was added to GEM-P in view of the presence of EBV + B cell clones. Overall response rate (RR) [complete response (CR) + partial response (PR)] was 73 % (95 % CI range 54-86 %). 11/29 (38 %) achieved CR and 10/29 (35 %) had PR. In first-line treatment, 4/10 patients achieved CR and 4/10 had PR relating to a RR of 80 %. CR was seen in 4/9 (45 %), 2/8 (25) and 1/2 (50 %) patients treated in the second, third and fifth-sixth line respectively. Thus, GEM-P was found to be effective as first-line or salvage therapy in T cell lymphoma.

Complications and toxicity after abdominal and pelvic hypoxic stop-flow perfusion chemotherapy: incidence and assessment of risk factors.

BACKGROUND: Controversial results regarding the efficacy and toxicity of hypoxic abdominal and pelvic stop-flow perfusion chemotherapy (SFP) have been reported in relatively small series. Hence, because adequate assessment of its benefit in large homogenous cohorts is missing, acceptable morbidity should initially be assured in a series of adequate size. Additionally, risk factors should be assessed for eventual patient selection. METHODS: The morbidity of abdominal and pelvic SFP performed on a miscellaneous group of patients in our institute was analyzed and potential risk factors for adverse events were evaluated. RESULTS: Seventy abdominal (n = 42) and pelvic (n = 28) SFP were performed on 55 patients. In total, 28 adverse effects were observed after 30% of the procedures. Severe (grade 3) adverse events were recorded only after 4% of the procedures, while treatment-related life-threatening events and deaths were not present. Abdominal procedures when compared with pelvic ones were associated with increased systemic toxicity (36 vs. 7%, p = 0.005). Advanced age, gender, prior chemotherapy and/or radiotherapy, limited experience, repeated procedure, drug choice and omission of hemofiltration after SFP completion were not associated with statistically significant increase of procedures with overall or systemic adverse events. CONCLUSIONS: In the present series, abdominal and pelvic SFP was associated with an acceptable morbidity, which was mostly mild or moderate. Abdominal procedures were associated with increased toxicity. This procedure seems to be repeatable and also well tolerated both by elderly patients and by patients who had undergone prior chemotherapy and/or radiotherapy, while hemofiltration does not appear to decrease the incidence of systemic toxicity.

Capecitabine non-adherence: exploration of magnitude, nature and contributing factors.

OBJECTIVES: The prescribing of oral chemotherapy agents previously available only in the intravenous formulation, such as capecitabine, has afforded many benefits including reduced administration costs and improved patient acceptability. However, it has introduced the new challenge of ensuring patient adherence to therapy. It is therefore necessary to quantify adherence, and with a view to improving services, explore factors that may impact on medication taking behavior. METHODS: Patients with a diagnosis of breast or colorectal cancer and prescribed capecitabine were recruited from a UK teaching hospital. Data regarding self-reported adherence, beliefs about medicines, side effects, and satisfaction with information received about capecitabine were recorded. RESULTS: Non-adherence was reported by 23.3% of the 43 participants. Capecitabine therapy was perceived necessary by 97.6%, but almost one-third of participants had strong concerns. Side effects were reported by 80% of participants, with Palmar-Plantar erythrodysesthesia and fatigue most troubling participants. Complete satisfaction with information received was reported by 65% of participants; however, dissatisfaction about how to tell if capecitabine is working and the proposed duration of therapy was expressed by 42.9% and 37.3% of participants, respectively. CONCLUSIONS: Adherence to capecitabine is high with a strong conviction that the therapy is necessary. However, concerns were expressed regarding the experience of side effects. Patients have unmet information needs regarding the processes involved with monitoring capecitabine efficacy and determination of therapy duration. Healthcare professionals may therefore wish to consider a greater focus on involving patients in the monitoring of their care with respect to efficacy and planned treatment schedules.

Multilevel latent variable models for global health-related quality of life assessment.

Quality of life (QOL) assessment is a key component of many clinical studies and frequently requires the use of single global summary measures that capture the overall balance of findings from a potentially wide-ranging assessment of QOL issues. We propose and evaluate an irregular multilevel latent variable model suitable for use as a global summary tool for health-related QOL assessments. The proposed model is a multiple indicator and multiple cause style of model with a two-level latent variable structure. We approach the modeling from a general multilevel modeling perspective, using a combination of random and nonrandom cluster types to accommodate the mixture of issues commonly evaluated in health-related QOL assessments--overall perceptions of QOL and health, along with specific psychological, physical, social, and functional issues. Using clinical trial data, we evaluate the merits and application of this approach in detail, both for mean global QOL and for change from baseline. We show that the proposed model generally performs well in comparing global patterns of treatment effect and provides more precise and reliable estimates than several common alternatives such as selecting from or averaging observed global item measures. A variety of computational methods could be used for estimation. We derived a closed-form expression for the marginal likelihood that can be used to obtain maximum likelihood parameter estimates when normality assumptions are reasonable. Our approach is useful for QOL evaluations aimed at pharmacoeconomic or individual clinical decision making and in obtaining summary QOL measures for use in quality-adjusted survival analyses.