Cost-effectiveness of Capecitabine + Irinotecan Versus Leucovorin + Fluorouracil + Irinotecan in the Second-line Treatment of Metastatic Colorectal Cancer in China.

PURPOSE: The AXEPT trial demonstrated that modified XELIRI (mXELIRI; capecitabine + irinotecan) was noninferior to standard treatment with FOLFIRI (fluorouracil + leucovorin + irinotecan), both ± bevacizumab, in the treatment of metastatic colorectal cancer (mCRC). The present study was designed to evaluate the cost-effectiveness of mXELIRI versus FOLFIRI as a second-line treatment of mCRC. METHODS: We developed a Markov model to estimate the costs and health outcomes of mXELIRI and FOLFIRI in patients with mCRC from the Chinese payer perspective. Survival data, transition probabilities, and health utility values were obtained from published studies. The costs of drugs were obtained from the West China Hospital. Life-years (LYs), quality-adjusted life-years (QALYs) gained, incremental cost-utility ratio (ICUR), and incremental cost-effectiveness ratio (ICER) values were regarded as the primary end points. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to evaluate the impact of uncertainty of parameters in the analysis. FINDINGS: The effectiveness was found to be 0.48 QALYs (1.14 LYs) in the mXELIRI arm and 0.41 QALYs (1.05 LYs) in the FOLFIRI arm, with total costs of 29,896.41 US dollars (USD) in the mXELIRI arm and 28,894.68 USD in the FOLFIRI arm. The ICER and ICUR with mXELIRI versus FOLFIRI were 11,130.33 USD/LY and 14,310.43 USD/QALY gained, which were less than the willingness-to-pay threshold in China (25,840.88 USD/QALY). IMPLICATIONS: Based on the results of this study, mXELIRI was found to be a cost-effective alternative to FOLFIRI as a second-line treatment of mCRC in patients in China.

Fast-track multidisciplinary treatment versus conventional treatment for colorectal cancer: a multicenter, open-label randomized controlled study.

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

5-Fluorouracil and Capecitabine: Assessment and Treatment of Uncommon Early-Onset Severe Toxicities Associated With Administration.

BACKGROUND: Uncommon early-onset severe toxicities from 5-fluorouracil (5-FU) and capecitabine can be fatal if early warning signs are not recognized and treated promptly. OBJECTIVES: This article delineates the differences between expected side effects and uncommon early-onset severe toxicities from 5-FU and capecitabine. It also provides background for understanding the reasons patients may develop these toxicities and reviews the efficacy of standard supportive care against a novel therapy (uridine triacetate). METHODS: A panel of nurses convened to review the literature about toxicities associated with 5-FU and capecitabine administration and determined methods to educate nurses about toxicities and treatment. FINDINGS: Standard supportive care for 5-FU and capecitabine toxicities is associated with high fatality rates. Uridine triacetate treatment within 96 hours of administration is associated with survival.

The Adjuvant Treatment of Stage III Colon Cancer: Might Less Be More?

Oxaliplatin-based chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin] or XELOX [oxaliplatin, capecitabine; also called CAPOX]) for 6 months is the current standard for adjuvant therapy of stage III colon cancer patients with good performance status. However, these regimens are associated with significant toxicities, including myelosuppression, diarrhea, and oxaliplatin-induced, cumulative, dose-dependent neurotoxicity. A reduced duration of adjuvant therapy, which would reduce overall toxicity while maintaining overall clinical efficacy, would be optimal. The goal of the International Duration Evaluation of Adjuvant (IDEA) study was to evaluate the noninferiority of 3-month compared with 6-month adjuvant oxaliplatin-based treatment in stage III colon cancer using a prospectively designed pooled analysis of 6 concurrently conducted phase III randomized trials. Herein, we review the findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy using patient-based risk factors.

Cost-effectiveness analysis of XELOX versus XELOX plus bevacizumab for metastatic colorectal cancer in a public hospital school.

BACKGROUND: Metastatic colorectal cancer imposes a substantial burden on patients and society. Over the last years, progresses in the treatment have been made especially due to the introduction of monoclonal antibodies, such as bevacizumab which, on the other hand, has considerably increased the costs of treatment. We performed a cost-effectiveness analysis of bevacizumab plus XELOX in comparison with XELOX alone in metastatic colorectal cancer in first-line therapy, from the perspective of a public hospital school in Brazil. METHODS: This was a cost-effectiveness analysis performed by a decision tree and Markov models. Costs were expressed in local currency and outcomes were expressed in months of life gained. The model was constructed using the TreeAge Pro 2013® software. RESULTS: The incremental difference in years of life gained was 2.25 months, with an extra cost of 47,833.57 BRL, resulting in an incremental cost-effectiveness of 21,231.43 BRL per month of life gained. CONCLUSIONS: Although the XELOX plus bevacizumab regimen is a more expensive and more effective treatment than XELOX, it does not fit the reimbursement values fixed by the public healthcare system in Brazil.

Pharmacologically Inactive Bisphosphonates as an Alternative Strategy for Targeting Osteoclasts: In Vivo Assessment of 5-Fluorodeoxyuridine-Alendronate in a Preclinical Model of Breast Cancer Bone Metastases.

Bisphosphonates have effects that are antiresorptive, antitumor, and antiapoptotic to osteoblasts and osteocytes, but an effective means of eliciting these multiple activities in the treatment of bone metastases has not been identified. Antimetabolite-bisphosphonate conjugates have potential for improved performance as a class of bone-specific antineoplastic drugs. The primary objective of the study was to determine whether an antimetabolite-bisphosphonate conjugate will preserve bone formation concomitant with antiresorptive and antitumor activity. 5-FdU-ale, a highly stable conjugate between the antimetabolite 5-fluoro-2'-deoxyuridine and the bisphosphonate alendronate, was tested for its therapeutic efficacy in a mouse model of MDA-MB231 breast cancer bone metastases. In vitro testing revealed osteoclasts to be highly sensitive to 5-FdU-ale. In contrast, osteoblasts had significantly reduced sensitivity. Tumor cells were resistant in vitro but in vivo tumor burden was nevertheless significantly reduced compared with untreated mice. Sensitivity to 5-FdU-ale was not mediated through inhibition of farnesyl diphosphate synthase activity, but cell cycle arrest was observed. Although serum tartrate-resistant acid phosphatase (TRAP) levels were greatly reduced by both drugs, there was no significant decrease in the serum bone formation marker osteocalcin with 5-FdU-ale treatment. In contrast, there was more than a fivefold decrease in serum osteocalcin levels with alendronate treatment (p < 0.001). This finding is supported by time-lapse micro-computed tomography analyses, which revealed bone formation volume to be on average 1.6-fold higher with 5-FdU-ale treatment compared with alendronate (p < 0.001). We conclude that 5-FdU-ale, which is a poor prenylation inhibitor but maintains potent antiresorptive activity, does not reduce bone formation and has cytostatic antitumor efficacy. These results document that conjugation of an antimetabolite with bisphosphonates offers flexibility in creating potent bone-targeting drugs with cytostatic, bone protection properties that show limited nephrotoxicity. This unique class of drugs may offer distinct advantages in the setting of targeted adjuvant therapy and chemoprevention of bone diseases. © 2016 American Society for Bone and Mineral Research.

Eficacia y seguridad de ramucirumab más paclitaxel em pacientes con cáncer gástrico o de la unión esofagogástrica metastásico o localmente avanzado irresecable, con progresión de la enfermedad luego de quimioterápia de primera línea a base de fluoropirimidinas y sales de platino / Efficacy and safety of ramucirumab plus paclitaxel in patients with gastric cancer or metastatic or locally advanced unresectable esophagogastric union, with progression of the disease after first-line chemotherapy with fluoropyrimidines and platinum salts

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad del ramucirumab más paclitaxel para el tratamiento de pacientes con cáncer gástrico o de la unión esófagogástrica metastásico o localmente avanzado irresecable, con progresión de la enfermedad luego de quimioterapia de primera línea a base de fluoropirimidinas y sales de platino. El cáncer gástrico es uno de los cánceres más frecuentes a nivel mundial. En el año 2012, la Agencia Internacional para la Investigación del Cáncer (IARC, por sus siglas en inglés) de la Organización Mundial de la Salud (OMS) estimó para Perú una incidencia de cáncer gástrico de 16,59 x 100,000 personas/año, con una prevalencia de 34,34 x 100,000 personas y una mortalidad de 13,06 x 100,000 personas/año. Además, en el 2015, el Instituto Nacional de Enfermedades Neoplásicas (INEN) del Perú reportó al cáncer gástrico como el tercer cáncer más frecuente en atención. TECNOLOGÍA SANITARIA DE INTERÉS: Ramucirumab (Cymraza, fabricado por Eli Lilly and Company) es un anticuerpo monoclonal recombinante que actúa contra el receptor VEGFR2 (Spratlin et al., 2010). Dicha unión evita que los ligandos VEGF-A, VEGF-C y VEGF-D desencadenen cascadas de proliferación y migración de células endoteliales reduciendo la vascularización y crecimiento tumoral. METODOLOGÍA: Se realizó una búsqueda bibliográfica con respecto a la eficacia y seguridad de ramucirumab en combinación con paclitaxel como tratamiento de segunda línea para pacientes adultos con cáncer gástrico o de la unión esofagogástrica metastásico o localmente avanzado irresecable, con progresión de la enfermedad luego de quimioterapia de primera línea a base de fluoropirimidinas y sales de platino. Esta búsqueda incluyó los siguientes metabuscadores y bases de datos: Medline/Pubmed, Traslating Research into Practice (TRIP Database), Cochrane Library, LILACS/Biblioteca Virtual de Salud, Center for Reviews and Dissemination Database (CRD Database), Ovid. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de ramucirumab más paclitaxel como tratamiento de pacientes adultos con cáncer gástrico o de la unión esofagogástrica metastásico o localmente avanzado irresecable, con progresión de la enfermedad luego de quimioterapia de primera línea a base de fluoropirimidinas y sales de platino. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). no existe evidencia fuerte en beneficios en la calidad de vida, ya que de los 15 dominios evaluados en el Cuestionario de la Calidad de Vida de la Organización Europea para la Investigación y Tratamiento del Cáncer (EORTC QLQ-C30, por sus siglas en inglés), sólo tres resultaron tener una diferencia estadísticamente significativa al tratamiento con ramucirumab más paclitaxel: las náuseas y vómitos, en el rol emocional y en las diarreas. Donde, el rol emocional y la aparición de náuseas y vómitos tienden a prolongar su aparición en los pacientes tratados con ramucirumab más paclitaxel, mientras que las diarreas tienden a presentarse antes. Asimismo, es de notar que los intervalos de confianza son bastantes cercanos al valor nulo de asociación (valor 1). Además, el decidir hacer un análisis de tiempo a evento es controversial en desenlaces como calidad de vida, debido a que los síntomas cambian en el tiempo, con lo cual estos podrían merecer un análisis de medidas repetidas. Más aun, la elección del modelo de Cox utilizado para estimar el HR de las curvas de tempo de deterioro según estado de performance no es el adecuado debido a que no se cumple con el supuesto de hazard proporcional (según lo observado en el gráfico de Kaplan-Meier). Por otro lado, a pesar de que no se han reportado valores de significancia estadística en la comparación de eventos entre grupos se observa una mayor frecuencia de eventos adversos de grado de severidad de 3 a más en el grupo de ramucirumab más paclitaxel. Por último, en la actualidad el Petitorio Farmacológico de EsSalud disponen de varias alternativas de tratamiento de segunda línea como paclitaxel, docetaxel, e irinotecán; las cuales al igual que la tecnología evaluada son recomendadas por las guías de práctica clínica internacionales para el manejo de pacientes com cáncer gástrico avanzado o de la unión esofagogástrica con la misma fuerza de recomendación. CONCLUSIÓN: El Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI no aprueba el uso de ramucirumab más paclitaxel para el manejo de pacientes con diagnóstico de cáncer gástrico o de la unión esofagogástrica metastásico o localmente avanzado irresecable, con progresión de la enfermedad luego de quimioterapia de primera línea a base de fluoropirimidinas y sales de platino.

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

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

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

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

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

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

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

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

Investigation of adverse-event-related costs for patients with metastatic breast cancer in a real-world setting.

BACKGROUND: Existing treatments for metastatic breast cancer (mBC) are often effective but can cause adverse events (AEs). This study aimed to identify AEs associated with chemotherapies commonly used in mBC treatment (phase 1) and to quantify the economic impact of these AEs (phase 2). MATERIALS AND METHODS: Patients in phase 1 had at least one claim for therapy for mBC, with at least one episode with single or multiple agents. The most common chemotherapy-related complications were identified using medical and pharmacy claims data. In phase 2, patients meeting study criteria were divided into four treatment cohorts by the line of treatment and chemotherapy received: first-line taxane-treated patients, second-line taxane-treated patients, first-line capecitabine-treated patients, and second-line capecitabine-treated patients. Average monthly AE-related health care costs per cohort were stratified by cost component. Total monthly costs per number of AEs were also calculated. RESULTS: On average, patients in phase 1 (n = 1,551) had 2 episodes of treatment, with a mean duration of 131 days. The most frequently noted complications were anemia (50.7% of mBC treatment episodes), bilirubin elevation (26.4%), and leukopenia (24.8%). In phase 2, costs related to AEs were primarily driven by incremental inpatient, outpatient, and pharmacy costs. Increases in average monthly costs ranged from $854 (9.0%) to $5,320 (69.5%), according to cohort. Overall costs increased with increasing numbers of AEs. CONCLUSION: Chemotherapy-related AEs in patients with mBC are associated with a substantial economic burden that increases with the number of AEs reported.

Efficacy and safety of single agent or combination adjuvant chemotherapy in elderly patients with colon cancer: a Canadian cancer institute experience.

BACKGROUND: The pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC. PATIENTS AND METHODS: A retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival. RESULTS: Two hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups. CONCLUSION: In elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC.

MRI and FDG-PET for assessment of response to neoadjuvant chemotherapy in locally advanced rectal cancer.

BACKGROUND: The purpose of this study was to assess the value of magnetic resonance imaging (MRI) and additional (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for tumor response to neoadjuvant chemotherapy (NAC) in patients with locally advanced rectal cancer (LARC). METHODS: Data on 40 patients with LARC, who were treated with NAC and underwent MRI and FDG-PET/CT before and after NAC, were analyzed retrospectively. Surgery was performed at a median of 6 weeks after NAC and the images were compared with the histological findings. The tumor regression grade 3/4 was classified as a responder. RESULTS: Sixteen patients were pathological responders. Receiver operating characteristic (ROC) analysis revealed that MRI total volume after NAC (MRI-TV2) and ΔMRI-TV had the highest performance to assess responders (area under the ROC curve [AUC] 0.849 and AUC 0.853, respectively). The reduction rate of the maximum standardized uptake value (ΔSUVmax) was also an informative factor (AUC 0.719). There seems no added value of adding FDG-PET/CT to MRI-TV2 and ΔMRI-TV in assessment of NAC responders judging from changes in AUC (AUC of ΔSUVmax and MRI-TV2 was 0.844, and AUC of ΔSUVmax and ΔMRI-TV was 0.846). CONCLUSIONS: MRI-TV2 and ΔMRI-TV were the most accurate factors to assess pathological response to NAC. Although ΔSUVmax by itself was also informative, the addition of FDG-PET/CT to MRI did not improve performance. Patients with LARC who were treated by induction chemotherapy should receive an MRI examination before and after NAC to assess treatment response. A more than 70 % volume reduction shown by MRI volumetry may justify the omission of subsequent radiotherapy.

The cost effectiveness of bevacizumab when added to capecitabine, with or without mitomycin-C, in first line treatment of metastatic colorectal cancer: results from the Australasian phase III MAX study.

BACKGROUND: Based on the clinical data, bevacizumab has been approved in Australia and globally for the treatment of advanced colorectal cancer. However, limited evidence exists for its cost-effectiveness. The purpose of this study was to evaluate the cost effectiveness of adding bevacizumab to capecitabine monotherapy in patients with metastatic colorectal cancer, using data from the prospective economic evaluation conducted alongside the MAX trial. METHODS: Individual patient level data on resource use and progression free survival were prospectively collected in the phase III MAX trial. Resource use data were collected for the period between randomisation and disease progression, and unit costs were assigned from the perspective of the Australian health care funder. Effectiveness was measured in quality adjusted progression free survival years, with utility scores obtained from both the community valued EQ-5D questionnaire and the patient valued UBQ-C questionnaire. Progression free survival was used as a secondary effectiveness measure. RESULTS: The addition of bevacizumab to capecitabine monotherapy cost approximately $192,156 (95% confidence interval [CI], $135,619 to $326,894) per quality adjusted progression free survival year gained when using publicly listed pharmaceutical prices and utility values from the EQ-5D questionnaire. This decreased to $149,455 (95% CI, $100,356 to $245,910) when values from the UBQ-C questionnaire were applied. The incremental cost per progression free survival year was $145,059 (95% CI, $106,703 to $233,225). CONCLUSIONS: Bevacizumab was not found to be cost effective at its listed price, based on results from the MAX trial.

Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal cancer: a phase 1 trial.

PURPOSE: The goal of this phase 1 trial was to determine the maximum tolerated dose (MTD) of concurrent capecitabine, bevacizumab, and erlotinib with preoperative radiation therapy for rectal cancer. METHODS AND MATERIALS: Patients with clinical stage II to III rectal adenocarcinoma, within 12 cm from the anal verge, were treated in 4 escalating dose levels, using the continual reassessment method. Patients received preoperative radiation therapy with concurrent bevacizumab (5 mg/kg intravenously every 2 weeks), erlotinib, and capecitabine. Capecitabine dose was increased from 650 mg/m(2) to 825 mg/m(2) orally twice daily on the days of radiation therapy; erlotinib dose was increased from 50 mg orally daily in weeks 1 to 3, to 50 mg daily in weeks 1 to 6, to 100 mg daily in weeks 1 to 6. Patients underwent surgery at least 9 weeks after the last dose of bevacizumab. RESULTS: A total of 19 patients were enrolled, and 18 patients were considered evaluable. No patient had grade 4 acute toxicity, and 1 patient had grade 3 acute toxicity (hypertension). The MTD was not reached. All 18 evaluable patients underwent surgery, with low anterior resection in 7 (39%), proctectomy with coloanal anastomosis in 4 patients (22%), posterior pelvic exenteration in 1 (6%), and abdominoperineal resection in 6 (33%). Of the 18 patients, 8 (44%) had pathologic complete response, and 1 had complete response of the primary tumor with positive nodes. Three patients (17%) had grade 3 postoperative complications (ileus, small bowel obstruction, and infection). With a median follow-up of 34 months, 1 patient developed distant metastasis, and no patient had local recurrence or died. The 3-year disease-free survival was 94%. CONCLUSIONS: The combination of preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib was well tolerated. The pathologic complete response rate appears promising and may warrant further investigation.

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.

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

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

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

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

Assessment of nutritional status in cancer--the relationship between body composition and pharmacokinetics.

Several nutritional assessment tools have been used in oncology settings to monitor nutritional status and its associated prognostic significance. Body composition is fundamental for the assessment of nutritional status. Recently, the use of accurate and precise body composition tools has significantly added to the value of nutritional assessment in this clinical setting. Computerized tomography (CT) is an example of a technique which provides state-of-the-art assessment of body composition. With use of CT images, a great variability in body composition of cancer patients has been identified even in people with identical body weight or body mass index. Severe muscle depletion (sarcopenia) has emerged as a prevalent body composition phenotype which is predictive of poor functional status, shorter time to tumor progression, shorter survival, and higher incidence of dose-limiting toxicity. Variability in body composition of cancer patients may be a source of disparities in the metabolism of cytotoxic agents. Future clinical trials investigating dose reductions in patients with sarcopenia and dose-escalating studies based on pre-treatment body composition assessment have the potential to alter cancer treatment paradigms.