Clasificación del daño tisular de antineoplásicos: Consenso del Grupo Español de Farmacia Oncológica / Classification of antineoplastic drug-induced tissue damage: a Consensus of the Spanish Oncology Pharmacy Group

Objetivo: Realizar un consenso de expertos utilizando el método Delphipara la clasificación del potencial de daño tisular de los antineoplásicosque facilite la toma de decisiones ante una extravasación.Método: El panel de evaluadores estaba formado por siete farmacéuticos del grupo de trabajo de extravasaciones. Otro actuó comocoordinador. Se revisó la probabilidad de daño tisular a partir de ochodocumentos de referencia. Se clasificaron en cuatro categorías: vesicante, irritante de alto riesgo, irritante de bajo riesgo y no irritante. Serealizaron dos rondas; tras éstas los fármacos con consenso < 70% sediscutieron en grupo de forma no anónima. Se analizó para cada ronda:la mediana del grado de consenso y ámbito intercuartílico (AIQ25-75),el grado de concordancia por categoría de daño tisular y el porcentaje de antineoplásicos con grado de consenso > 85% y del 100%.Se analizaron de forma separada los fármacos con discordancias declasificación entre los documentos consultados. Se utilizó el programaestadístico SPSS v23.0. (AU)

Objective: To reach at an expert consensus, using the Delphi method, forclassifying the tissue-damaging potential of antineoplastic drugs, in order tofacilitate the decision-making process in the event of extravasations.Method: The panel of expert evaluators was made up of seven pharmacists belonging to the working group on extravasations. Other memberserved as coordinator. The likelihood of tissue damage was reviewed on thebasis of eight reference documents. Four categories of drugs were established: vesicant (V); high risk irritant (HRI); low risk irritant (LRI) and non-irritant(NI). Two rounds of surveys were performed. The drugs with an agreementof less than 70% after the two rounds were discussed non-anonymously by thegroup. For each of the rounds the following was analysed: median ofthe degree of consensus and the interquartile range (IQR25-75), degreeof agreement by tissue damage category, and percentage of antineoplastics reaching a degree of consensus of over 85% and of 100%. Drugswhose classification differed in the various reference documents were assessed separately. SPSS v23.0 statistical software was used. (AU)

Classification of antineoplastic drug-induced tissue damage: a Consensus of the Spanish Oncology Pharmacy Group.

OBJECTIVE: To reach at an expert consensus, using the Delphi method, for classifying the tissue-damaging potential of antineoplastic drugs, in  order to facilitate the decision-making process in the event of  extravasations. METHOD: The panel of expert evaluators was made up of seven  pharmacists belonging to the working group on extravasations. Other  member served as coordinator. The likelihood of tissue damage was  reviewed on the basis of eight reference documents. Four categories of  drugs were established: vesicant (V); high risk irritant (HRI); low risk  irritant (LRI) and non-irritant (NI). Two rounds of surveys were performed. The drugs with an agreement of less than 70% after the two rounds were  discussed non-anonymously by the group. For each of the rounds the  following was analysed: median of the degree of consensus and the  interquartile range (IQR25-75), degree of agreement by tissue damage  category, and percentage of antineoplastics reaching a degree of  consensus of over 85% and of 100%. Drugs whose classification differed in the various reference documents were assessed separately. SPSS v23.0  statistical software was used. RESULTS: Seventy-one antineoplastics were evaluated. In the first round, the median for degree of consensus was 100.0% (IQR25-75: 71.4- 100.0%). In the second round, the median was 100.0% (IQR25-75: 85.7- 100.0%). The percentage of antineoplastics with a consensus of 85.7% or  above increased from 66.7% to 85.9% in the second round. For the 30  antineoplastics whose values differed in the reference documents, the  degree of agreement increased from 71.4% (IQR25-75: 57.1-87.7%) to  100.0% (IQR25-75: 85.7-100.0%) in the second round. The percentage of antineoplastics with a consensus of 85.7% or above increased from 40.0%  to 76.7%. Four antineoplastics had a degree of agreement of less  than 70.0%. The final classification of drugs per category, was: 17  vesicants; 15 HRI; 13 LRI; and 26 NI. The final degree of consensus was  85.7% or above for 90.1% of antineoplastics, and 100.0% for 74.6% of  the same. CONCLUSIONS: In this area of scarce evidence and high variability, the Delphi method allows for consensus in classifying tissue damage risk,  thus making it easier to reach clinical decisions. In approximately 90% of  the antineoplastics, the degree of consensus reached by the expert panel  was 85% or above. In 74% of the antineoplastics, it was 100%. This  provides solid ground for management decisions.

Objetivo: Realizar un consenso de expertos utilizando el método Delphi para la clasificación del potencial de daño tisular de los  antineoplásicos que facilite la toma de decisiones ante una extravasación.Método: El panel de evaluadores estaba formado por siete farmacéuticos del grupo de trabajo de extravasaciones. Otro actuó como coordinador. Se revisó la probabilidad de daño tisular a partir de  ocho documentos de referencia. Se clasificaron en cuatro categorías:  vesicante, irritante de alto riesgo, irritante de bajo riesgo y no irritante. Se realizaron dos rondas; tras éstas los fármacos con consenso < 70% se discutieron en grupo de forma no anónima. Se analizó para cada ronda: la mediana del grado de consenso y ámbito intercuartílico (AIQ25- 75), el grado de concordancia por categoría de daño tisular y el porcentaje de antineoplásicos con grado de consenso > 85% y del 100%. Se analizaron de forma separada los fármacos con discordancias de clasificación entre los documentos consultados. Se utilizó el programa estadístico SPSS v23.0.Resultados: Se evaluaron 71 antineoplásicos. En la primera ronda la mediana del grado de consenso fue 100% (AIQ25-75: 71,4-100,0%) y  en la segunda ronda 100% (AIQ25-75: 85,7-100,0%). El porcentaje de  antineoplásicos con consenso ≥ 85,7% aumentó del 66,7% al 85,9% en la segunda ronda. Para los 30 antineoplásicos con discrepancias entre los  documentos revisados, el grado de consenso aumentó del 71,4% (AIQ25- 75: 57,1-87,7%) al 100% (AIQ25-75: 85,7-100,0%) en la segunda ronda. El porcentaje de antineoplásicos con concordancia ≥ 85,7% pasó del  40,0% al 76,7%. Cuatro antineoplásicos presentaron consenso < 70%. La  clasificación final incluyó 17 fármacos como vesicantes, 15 como irritantes  de alto riesgo, 13 como irritantes de bajo riesgo y 26 como no irritantes. El grado de acuerdo final fue ≥ 85,7% en el 90,1% de los antineoplásicos y  del 100% en el 74,6%.Conclusiones: En este área de escasa evidencia y variabilidad la metodología Delphi permite alcanzar un consenso de clasificación del riesgo de daño tisular que facilita la toma de decisiones.  Aproximadamente para el 90% de los antineoplásicos el grado de  concordancia alcanzado por el panel de expertos fue > 85%, y para el  74% de los antineoplásicos la concordancia fue del 100%, aportando una  base sólida para las decisiones de manejo.

Adherence and adverse events of intraperitoneal chemotherapy in optimally debulked ovarian cancer patients: Real-life study.

PURPOSE: Intraperitoneal with intravenous chemotherapy (IP/IV) is the recommended option for patients with stage III cancer with optimally debulked (<1 cm residual) disease based on randomized controlled trials and showing important improvements in overall survival and progression free survival. However, its application has not been largely adopted due to its difficult administration that requires a trained nurse staff. The aim of this work was to study the completion and the toxicity of an IP outpatient chemotherapy regimen in optimally debulked stage III ovarian cancer patients. METHODS: A single-center, retrospective observational study in women with stage III ovarian cancer following optimal cytoreductive surgery (<1 cm) followed by IP/IV chemotherapy from 2009 to 2017. The IP/IV regimen was as it follows: IV paclitaxel 175 mg/m2 in 3 h, day 1; IP cisplatin (100 mg/m2-until December 2013-or 75 mg/m2), day 2; IP paclitaxel 60 mg/m2, day 8, each 21 days for six cycles. RESULTS: A total of 60 patients received IP/IV regimen. Of these, 41 patients (68.3%) completed the six IP chemotherapy cycles and 51 (84.9%) completed four or more cycles. Most of the adverse events reported were non-hematological and G1-2. There was no difference neither in adherence nor in the frequency of adverse events between both cisplatin groups. Despite a high rate of adverse events, IP chemotherapy can be delivered with a high completion rate and manageable toxicity to patients with optimally debulked ovarian cancer.

Quantitative and qualitative control of antineoplastic preparations: Gravimetry versus HPLC.

This article compares gravimetry vs. high-performance liquid chromatography (HPLC) as quality control (QC) methods for paclitaxel, docetaxel and oxaliplatin preparations. We aimed at assessing the preparation method reliability in our hospital, evaluating compounding accuracy and estimating the influence of personnel training and standardized homogenization on compounding accuracy. Agreement, correlation, concordance, accuracy and precision between methods were evaluated for each drug. Conforming preparation percentages (CPs) at different tolerance limits (TLs) and compounding accuracy were calculated for each method and drug. Compounding accuracy was compared before and after personnel training and standardized homogenization implantation. SPSS v 20.0 and Ene v 2.0 were used. A total of 222 samples (58 docetaxel, 95 paclitaxel and 69 oxaliplatin) were analyzed. Gravimetry and HPLC are comparable methods. Overall CP was 81% for gravimetry at 10% TL and 85% for HPLC at 15% TL. Compounding accuracy is shown to be good for all methods and drugs. Homogenization optimization and personnel training make measurements more accurate for docetaxel and paclitaxel HPLC, but seem to worsen accuracy for docetaxel gravimetry. Gravimetry has shown to be a good alternative to HPLC for routine QC. Coupling with electronic methods should be considered in the future.

BK Virus-Associated Hemorrhagic Cystitis After Allogeneic Hematopoietic Stem Cell Transplantation in the Pediatric Population.

OBJECTIVE: To study the incidence, risk factors, and treatment of hemorrhagic cystitis secondary to BK-virus reactivation (HC-BKV) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the pediatric population. METHODS: Case-control study in which all pediatric patients (0-18 years) who underwent allo-HSCT from September 2009 to January 2014 were followed. RESULTS: Twenty-nine patients underwent an allo-HSCT. The median age was 9 years (range = 6 months to 15 years), 61% male. The primary diagnosis was acute lymphoblastic leukemia (72.4%). Six (20.7%) developed HC-BKV. In a multivariate analysis of risk factors, it was observed that the reactivation of BK virus was associated with age more than 10 years ( P = .098) and those with positive serology for Epstein-Barr virus ( P = .06). Five of the 6 patients with HC-BKV received cidofovir (CDV) at doses of 3 to 5 mg/kg/week. The treatment lasted a median of 3 cycles (range = 2-5). One of the patients (20%) developed nephrotoxicity. Of the 5 patients treated with CDV, 3 (60%) had a complete response, 1 (20%) partial response, and 1 (20%) no response. CONCLUSION: We conclude that HC-BKV is a frequent complication after allo-HSCT. CDV therapy can be effective but controlled clinical trials are needed.

[Applying dose banding to the production of antineoplastic drugs: a narrative review of the literature]. / Dose banding aplicado a la elaboración de antineoplásicos: una revisión narrativa de la literatura.

The dosage of antineoplastic drugs has historically been based on individualized prescription and preparation according to body surface area or patient´s weight. Lack of resources and increased assistance workload in the areas where chemotherapy is made, are leading to the development of new systems to optimize the processing without reducing safety. One of the strategies that has been proposed is the elaboration by dose banding. This new approach standardizes the antineoplastic agents doses by making ranges or bands accepting a percentage of maximum variation. It aims to reduce processing time with the consequent reduction in waiting time for patients; to reduce errors in the manufacturing process and to promote the rational drug use. In conclusion, dose banding is a suitable method for optimizing the development of anticancer drugs, obtaining reductions in oncologic patients waiting time but without actually causing a favorable impact on direct or indirect costs.

La dosificación de los fármacos antineoplásicos se ha basado históricamente en la prescripción y elaboración individualizada según la superficie corporal o peso del paciente. La falta de recursos y el aumento de la carga asistencial en las áreas de elaboración de quimioterapia están propiciando que se desarrollen nuevos sistemas que optimicen la elaboración sin reducir la seguridad. Una de las estrategias que se ha propuesto es la elaboración mediante dose banding. Este nuevo enfoque estandariza las dosis de antineoplásicos en rangos o bandas aceptando un porcentaje de variación máxima. Pretende reducir los tiempos de elaboración con la consiguiente reducción de los tiempos de espera de los pacientes, disminuir los errores en la elaboración y fomentar el uso racional de los fármacos. En definitiva, el dose banding es un método adecuado para la optimización de la elaboración de antineoplásicos, obteniendo reducciones del tiempo de espera de los pacientes oncológicos, aunque sin llegar a causar un impacto favorable sobre los costes directos o indirectos.

Dose banding aplicado a la elaboración de antineoplásicos: una revisión narrativa de la literatura / Applying dose banding to the production of antineoplastic drugs: a narrative review of the literature

La dosificación de los fármacos antineoplásicos se ha basado históricamente en la prescripción y elaboración individualizada según la superficie corporal o peso del paciente. La falta de recursos y el aumento de la carga asistencial en las áreas de elaboración de quimioterapia están propiciando que se desarrollen nuevos sistemas que optimicen la elaboración sin reducir la seguridad. Una de las estrategias que se ha propuesto es la elaboración mediante dose banding. Este nuevo enfoque estandariza las dosis de antineoplásicos en rangos o bandas aceptando un porcentaje de variación máxima. Pretende reducir los tiempos de elaboración con la consiguiente reducción de los tiempos de espera de los pacientes, disminuir los errores en la elaboración y fomentar el uso racional de los fármacos. En definitiva, el dose banding es un método adecuado para la optimización de la elaboración de antineoplásicos, obteniendo reducciones del tiempo de espera de los pacientes oncológicos, aunque sin llegar a causar un impacto favorable sobre los costes directos o indirectos (AU)

The dosage of antineoplastic drugs has historically been based on individualized prescription and preparation according to body surface area or patient ́s weight. Lack of resources and increased assistance workload in the areas where chemotherapy is made, are leading to the development of new systems to optimize the processing without reducing safety. One of the strategies that has been proposed is the elaboration by dose banding. This new approach standardizes the antineoplastic agents doses by making ranges or bands accepting a percentage of maximum variation. It aims to reduce processing time with the consequent reduction in waiting time for patients; to reduce errors in the manufacturing process and to promote the rational drug use. In conclusion, dose banding is a suitable method for optimizing the development of anticancer drugs, obtaining reductions in oncologic patients waiting time but without actually causing a favorable impact on direct or indirect costs (AU)

Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer.

PURPOSE: To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population. METHODS: Controlled, nonrandomized retrospective observational study. Treatment-naïve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007-December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). STATISTICAL ANALYSIS: median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test). RESULTS: In all, 69 patients were included: 32 (57.2 years -95%CI: 54.0-60.5-, 65.6% men) in CPT-FUFA group and 37 (68.1 years - 95%CI: 65.5-70.7-, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1-12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6-12.6) in bevacizumab_CPT-FUFA (hazard ratio = 1.22; 95%CI: 0.7-2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4-20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8-35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4-50) in 20/37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8-14,532.1) euros/patient. CONCLUSION: The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progression-free survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.

Multidisciplinary system for detecting medication errors in antineoplastic chemotherapy.

OBJECTIVE: To analyze medication errors (MEs) in a multidisciplinary system with a Computerized Pharmacotherapy Process (CPP) in cancer patients. DESIGN: A longitudinal, prospective 2-year (January 2003 -to December 2004) cohort study was made in adult patients administered antineoplastic treatment in Services of Oncology and Haematology. MEs were identified by double cross-validation of each stage of the pharmacotherapeutic process (prescription, preparation, dispensing, administration, and follow-up) carried out by the multidisciplinary team (physician, pharmacist, nurse) with CPP assistance. VARIABLES: Number of MEs per 1000 patient-days, percentage according to the stage of the pharmacotherapeutic process and the severity of intercepted ME (scored from 1 = no damage to the patient, to 5 = patient death). RESULTS: A total of 1311 patients were receiving treatment, and MEs were identified in 225. Out of a total of 13,158 patient-days, 276 MEs were detected, equivalent to 20.9 MEs per 1000 patient-days; of these, 16.8 MEs per 1000 patient-days (80%) were intercepted and did not affect any patient. The detected ME distribution according to pharmacotherapeutic stage was: prescription 75.7%, preparation 21.0%, dispensing 1.8%, administration 1.1%, and follow-up 0.4%. ME distribution according to severity was: grade 1 : 15.9%, grade 2 : 49.6%, grade 3 : 33.7%, grade 4 : 0.7%, and grade 5 : 0%. The system intercepted 98.9% of all MEs with severity >or=3 (MEs with a potential for causing patient damage). CONCLUSIONS: The multidisciplinary system with a well-established CPP detects 20.9 MEs per 1000 patient-days and intercepts 98.8% of all MEs with a potential for causing patient damage.

Pharmaceutical validation as a process of improving the quality of antineoplastic treatment.

OBJECTIVE: To quantify the improvement added by standardization of pharmaceutical validation (PV) of antineoplastic treatment to the processes of prescription and preparation of the pharmacotherapeutic sequence, in terms of prevention and reduction of medication errors (ME). DESIGN: Prospective cohort study during two years (from 2001-2002) for oncohaematologic patients (inpatients and outpatients) that compared the percentage of medication errors detected and resolved and the number of medication errors with potential clinical significance (severity value >or=4) intercepted during PV in both years. RESULTS: During the PV processes, 202 ME were identified and resolved, which is the equivalent of 16.88 ME/1,000 patient-days. In 2001 14.08 ME/1,000 patient-days were detected and 19.83 ME/1,000 patient-days in 2002. This means that the effectiveness of the identification method increased by 41%. The number of ME intercepted with clinical significance (severity value >or=4) increased in a statistically significant manner by 2.18 times in 2002. CONCLUSION: This study shows that the standardization of PV is an effective method of improving the quality of antineoplastic treatment use, by increasing the ability to intercept ME.