Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy.

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114 patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade 2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

Venous thromboembolism following L-asparaginase treatment for lymphoid malignancies in Korea.

Essentials Data on venous thromboembolism (VTE) after L-asparaginase (L-asp) in Asian lymphoma are scarce. This is a population-based study in Asian patients with lymphoid disease and L-asp-related VTE. The overall incidence of L-asp-associated VTE was similar to reports on Caucasians. This first and largest study in Asians shows that mainly adult patients are at risk of thrombosis. SUMMARY: Background L-asparaginase (L-asp)-associated venous thromboembolism (VTE) is a serious adverse complication associated with acute lymphoblastic leukemia (ALL) and lymphoma treatment. The incidence rate of L-asp-related VTE in Asian cancer patients is not well known. Methods We performed a population-based study between 2009 and 2013 using claim databases, including both diagnostic and medication codes, such as anti-cancer treatment with L-asp and VTE diagnoses from the starting date until 3 months after cessation of L-asp. Results A total of 3286 patients were prescribed L-asp treatment for any type of lymphoid malignancy including ALL and lymphoma; 116 patients (3.5%) experienced VTE. The most common site of thrombosis was the upper extremities (34.5%). Cerebral vein thrombosis (1.7%) occurred in two pediatric patients; 2.4% (43/1795) of pediatric patients and 4.9% (72/1486) of adult patients suffered from VTE, respectively; 2.7% (56/2064) of ALL and 4.9% (59/1217) of lymphoma patients were diagnosed with VTE after L-asp exposure. After univariate analysis, both the diagnosis of lymphoma (vs. ALL) and being an adult patient (vs. pediatric patient) were risk factors for VTE occurrence. However, after multivariate analysis, only age > 18 remained a risk factor for VTE (odds ratio, 1.79; 95% confidence interval, 1.14-2.81). Conclusions This is the first and largest population-based study in Asian patients with lymphoid malignancies treated with L-asp demonstrating that adult patients are at elevated risk of thrombosis after L-asp exposure. The overall incidence of L-asp-related VTE amongst these patients was similar to that in Caucasian populations.

Incidence of venous thromboembolism following major surgery in Korea: from the Health Insurance Review and Assessment Service database.

BACKGROUND: Data on the incidence of venous thromboembolism (VTE) following major surgery in Asian populations are limited. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we performed a nationwide population-based epidemiologic study to estimate the incidence of VTE after major orthopedic, cancer, and benign surgeries. VTE cases were identified from all patients undergoing major surgery between 2007 and 2011 using both diagnostic and drug codes as treatment evidence of VTE within 5 weeks of surgery. We also calculated the relative risk of VTE in major orthopedic and cancer surgery compared to benign surgery. RESULTS: The overall rates of postoperative VTE were 1.24%, 0.67%, and 0.05% for major orthopedic, cancer, and benign surgeries, respectively. Hip fracture (1.60%) and colorectal cancer surgeries (1.67%) were associated with the highest rates of VTE, and the rates steadily increased during the study period. Advanced age, female sex, and general anesthesia were independent risk factors for VTE. Patients undergoing surgery for colorectal, pancreatic, ovarian, and esophageal cancer, and major orthopedic surgery had a > 20-fold higher risk of VTE than those undergoing benign surgery. CONCLUSIONS: This is the largest epidemiologic study to investigate the incidence of VTE after major surgery in Asia, demonstrating that the rates of postoperative VTE are lower than in Caucasian populations. This study contributes to a better understanding of the differences in postoperative VTE development between Korean and Caucasian populations; the data also suggest that perioperative prophylactic strategies in Asians should be based on studies of such populations.

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients.

BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Adjuvant capecitabine chemotherapy using a tailored-dose strategy in elderly patients with colon cancer.

BACKGROUND: This study was conducted to analyze the feasibility of adjuvant capecitabine therapy using a tailored-dose escalation strategy in elderly patients with colon cancer (CC). METHODS: CC patients (≥ 70 years of age) who received adjuvant capecitabine were enrolled. The starting dosage of capecitabine was 2000 mg/m(2)/day (days 1-14, every 3 weeks). On the second cycle, the dosage was escalated to 2500 mg/m(2)/day if the patient tolerated the first cycle. Dose intensity (DI), toxicity, and the change in quality of life (QoL) were evaluated. RESULTS: Of 82 patients enrolled, 67 completed eight cycles. Dose escalation to 2500 mg/m(2)/day was possible in 56 patients, and this dosage was maintained in 24 patients until the completion of chemotherapy (eight cycles). Forty-one patients completed therapy with a DI ≥ 1333 mg/m(2)/day [relative dose intensity (RDI) ≥ 80%]. Toxic effects were tolerable and the QoL was not compromised during treatment. Creatinine clearance < 50 ml/min and Charlson-Age comorbidity index ≥ 8 were related to a reduced capecitabine dosage (RDI < 80%). CONCLUSIONS: A tailored-dose escalation strategy was feasible in elderly CC patients receiving adjuvant capecitabine chemotherapy. Decreased renal function and an increased number of comorbidities were independently predictive of reduced administration of the capecitabine dose.

Immunoglobulin D multiple myeloma: response to therapy, survival, and prognostic factors in 75 patients.

BACKGROUND: To analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM). DESIGN AND METHODS: Seventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr). RESULTS: Median age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum ß(2) microglobulin level, and platelet count were significant prognostic factors for OS. CONCLUSIONS: IgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.

Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database.

BACKGROUND: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a major health concern in Caucasians. Although the incidence of VTE is generally known to be lower in Asians than in Caucasians, results of epidemiologic studies among Asians have been conflicting. In this study we performed a nationwide population-based epidemiologic study to provide basic information regarding the incidence of VTE in the Korean population. METHODS: Using the Korean Health Insurance Review and Assessment Service (HIRA) database, VTE patients from 2004 to 2008 were retrospectively identified by both diagnostic codes and medication codes for drugs used in initial treatment of VTE. RESULTS: The respective age- and sex-adjusted annual incidences of VTE, DVT and PE per 100,000 individuals increased significantly from 8.83, 3.91 and 3.74 in 2004 to 13.8, 5.31 and 7.01 in 2008 (P = 0.0001), with successive increments each year. All three annual incidences also increased steadily with age (P = 0.0001 for all), particularly among those over 60 years old. CONCLUSIONS: This represents the largest epidemiologic study that demonstrates a lower incidence of VTE in Asian compared with Western populations; however, it also demonstrates a yearly increasing incidence of VTE in the Korean population.

The incidence, risk factors and prognostic implications of venous thromboembolism in patients with gastric cancer.

BACKGROUND: Data on venous thromboembolism (VTE) in gastric cancer (GC) are very scarce. OBJECTIVE: To investigate the incidence, risk factors and prognostic implications of VTE in Asian GC patients. METHODS: Prospective databases containing clinical information on GC patients (n = 2,085) were used. RESULTS: The 2-year cumulative incidences of all VTE events were 0.5%, 3.5% and 24.4% in stages I, II-IV(M0) and IV(M1), respectively. Advanced stage, older age and no major surgery were independent risk factors for developing VTE. When the VTE cases were classified into extremity venous thrombosis (EVT), pulmonary thromboembolism (PTE) or intra-abdominal venous thrombosis (IVT), IVTs (62%) were more common than EVTs (21%) or PTEs (17%). Although peri-operative pharmacologic thromboprophylaxis was not routinely administered, the VTE incidence after major surgery was only 0.2%. During chemotherapy, EVT/PTE developed more frequently than IVT (54% vs. 19%); however, during untreated or treatment-refractory periods, IVT developed more frequently than EVT/PTE (69% vs. 36%). In multivariate models, the development of EVT/PTE was a significant predictor of early death when compared with no occurrence of VTE (P < 0.05). However, IVT did not affect survival. CONCLUSION: This is the largest study that specially focused on VTE in GC and the VTE incidence in Asian GC patients was first demonstrated. Considering the low incidence of post-operative VTE development, the necessity of peri-operative pharmacologic thromboprophylaxis should be evaluated separately in Asian patients. The clinical situation of the development of EVT/PTE and IVT differed. Only EVT/PTE had an adverse effect on survival and IVT had no prognostic significance.

High-dose chemotherapy with autologous stem cell transplantation in extranodal NK/T-cell lymphoma: a retrospective comparison with non-transplantation cases.

To determine the role of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in extranodal NK/T-cell lymphoma patients, we conducted a retrospective analysis. In our previous study, we searched for patients who had received HDC/ASCT and identified 16 eligible patients and compared the treatment outcome with historical control group (n=246). Nine patients received HDC/ASCT in the first (CR1) or second complete remission (CR2), while seven patients received HDC/ASCT as salvage. Twelve of 16 patients achieved or maintained CR after HDC/ASCT. Among the 12 patients, five patients relapsed. Estimated 2-year overall survival (OS) and relapse-free survival (RFS) rates were 71.3+/-12.4% and 25.8+/-14.3%, respectively. There was a tendency of better survival in patients who received HDC/ASCT as compared to those who did not (P=0.091). In subset analysis, patients who underwent HDC/ASCT at CR (P=0.049) and patients with stage III or IV (P=0.001) had a favorable outcome. Patients with NKIPI 3,4 or EUNKTL, who underwent HDC/ASCT had more prolonged survival without statistical significance (P=0.055 and 0.056). In conclusion, HDC/ASCT may be considered as a treatment option for patients with extranodal NK/T-cell lymphoma, especially those in CR, with advanced disease (stage III/IV or EUNKTL) and high NKIPI scores.

Validation of the Korean version of the EORTC QLQ-C30.

This study evaluated the Korean version of the EORTC QLQ-C30 (version 3.0) in terms of psychometric properties and its validation. One hundred and seventy patients completed three questionnaires EORTC QLQ-C30, the Beck depression inventory (BDI), and a brief pain inventory (BPI). Multitrait scaling analyses demonstrated that all scales met multidimensional conceptualization criteria, in terms of convergence and discrimination validity. Cronbach's alpha coefficients for eight multiple-item scales were greater than 0.70, with the exception of cognitive functioning. All interscale correlations were statistically significant in the expected direction (p < 0.01). Multivariate analyses showed that physical and emotional functioning were significant explanatory variables for the global quality-of-life (QOL) scale (regression coefficients: 0.36, p < 0.001; and 0.37, p < 0.001; respectively). All scales were significantly associated with pain severity and interference of the BPI, and with the cognitive-affective and somatic scales of the BDI. The emotional-functioning scale was substantially correlated with the cognitive-affective scale and somatic scale of the BDI. These results demonstrate that the Korean version of the EORTC QLQ-C30 is a valid instrument for evaluating Korean-speaking patients with cancer, and can be used to distinguish clearly between subgroups of patients of differing performance status.

Allogeneic bone marrow transplantation for chronic myeloid leukemia: a retrospective study of busulfan-cytoxan versus total body irradiation-cytoxan as preparative regimen in Koreans.

From January 1990 to December 1997, 53 Korean patients with chronic myeloid leukemia (CML) receiving bone marrow transplantation (BMT) from human leucocyte antigen (HLA)-identical sibling donors conditioned with either busulfan and cyclophosphamide (BU/CY regimen) or total body irradiation and cyclophosphamide (TBI/CY regimen) were compared retrospectively. Transplantation-related mortality was 19% in BU/CY and 12% in TBI/CY, and early death (<100 d) occurred in 3 patients conditioned with BU/CY. Grade II-IV acute graft-versus-host disease (GVHD) was 9% of BU/CY and 52% of TBI/CY patients. Overall incidence of chronic GVHD was 50% of BU/CY and 52% of TBI/CY patients. In patients with chronic phase, 5-yr overall survival was 73% in the BU/CY group compared with 87% in the TBI/CY group (p=NS), and overall disease-free survival was 75% in the BU/CY group and 59% in the TBI/CY group (p=NS). So far, with a median follow-up of 45 months, 11 patients have relapsed; three relapses occurred after BU/CY and 8 after TBI/CY. The actuarial 5-yr relapse rate was 15% after BU/CY, 34% after TBI/CY (p=0.46). For patients transplanted in chronic phase within 1 yr after diagnosis, there was a clear trend for a lower relapse rate in the BU/CY group (5-yr relapse rate 0%) compared with the TBI/CY group (5-yr relapse rate 30%). The BU/CY group had similar BMT-related toxicity and similar overall survival and showed a clear trend of low relapse compared with the TBI/CY group. Therefore, BU/CY is an acceptable alternative for patients with CML during HLA-identical sibling allogeneic BMT.

Combination Chemotherapy of Oxaliplatin, 5-Fluorouracil, and Leucovorin in 5-Fluorouracil-Pretreated Patients with Metastatic Colorectal Cancer.

PURPOSE: To evaluate the efficacy and toxicity of oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in patients with metastatic colorectal cancer who previously treated with 5-FU-based chemotherapy. MATERIALS AND METHODS: Between April 1999 and January 2001, thirty-two patients were enrolled in this study. Oxaliplatin 130 mg/m2 was given intravenously (IV) on day 1 as was 5-FU 500 mg/m2 IV followed by continuous infusion of 5-FU 3,000 mg/m2 and LV 100 mg/m2 for 48 hours administered every 3 weeks. Six patients had received 5-FU as an adjuvant setting and 26 patients as a palliative regimen. RESULTS: The median age of the patients was 50 years (range; 19-69) and the dominant sites of metastasis were the liver, lung or both in 9, 5 and 2 patients respectively. In 30 evaluable patients, the overall response rate was 27% including 1 complete response and 7 partial responses. The median response duration was 28 weeks (95% confidence interval; 22~34 weeks) and the median progression free survival of all patients was 24 weeks (95% confidence interval; 15~33 weeks). A median 5 cycles (range; 2~9) and total 155 cycles were performed in 32 patients. 150 cycles were evaluable for toxicity. The most common hematologic toxicity was grade 1~2 anemia in 78 cycles (52%). Leukopenia (39%) and thrombocytopenia (23%) were fully reversible. The most common non-hematologic toxicity was nausea/vomiting (43/30%) followed by diarrhea (23%), hepatotoxicity (21%) and neurotoxicity (21%). One patient ceased therapy due to grade 4 diarrhea. No other severe toxicity interrupted this treatment. CONCLUSION: Oxaliplatin, 5-FU and LV in combination showed significant activity in previously treated metastatic colorectal cancer with favorable toxicity.

Adjuvant doxorubicin and cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in premenopausal women with axillary lymph node positive breast carcinoma.

BACKGROUND: This randomized controlled trial was to determine whether a combination chemotherapy regimen that contains anthracycline (doxorubicin and cyclophosphamide [AC]) is superior to the conventional cyclophosphamide, methotrexate, and 5-fluorouracil [CMF] combination in premenopausal women with axillary lymph node positive Stage II breast carcinoma. METHODS: Premenopausal women with lymph node positive breast carcinoma were stratified according to age (younger than 35 or 35 years or older) and the number of positive axillary lymph nodes (1-3, 4-9, or >/= 10) and then randomly assigned to receive either doxorubicin 40 mg/m(2) and cyclophosphamide 600 mg/m(2) intravenously (i.v.) every 3 weeks or cyclophosphamide 100 mg/m(2) orally on Days 1 through 14, methotrexate 40 mg/m(2) and 5-fluorouracil 500 mg/m(2) i.v. on Days 1 and 8 every 4 weeks. Both arms were scheduled for six cycles. RESULTS: The median follow-up was 57 months. Eighteen of the 55 AC patients developed recurrence compared with 16 of the 69 CMF patients. The corresponding 5-year recurrence free survival rates were 64% and 78%, respectively (P = 0.12). The site of the first recurrence for AC patients was locoregional in 7%, distant in 22%, and combined in 4%. The corresponding data for the CMF arm were 4%, 16%, and 3%, respectively. Six AC patients died compared with 9 CMF patients. The corresponding 5-year survival rates were 90% and 86%, respectively (P = 0.96). More leukopenia (52%, mostly Grade 1-2) occurred in the CMF arm than in the AC arm (33%, P = 0.001), but no febrile episode was accompanied with leukopenia. CONCLUSIONS: This study showed no difference between AC and CMF with respect to both disease free and overall survival rates in premenopausal women with axillary lymph node positive breast carcinoma.