Continuous infusion intermediate-dose cytarabine, mitoxantrone, plus etoposide for refractory or early relapsed acute myelogenous leukemia.

For refractory and early relapsed AML, this prospective phase II clinical trial evaluated a salvage chemotherapy regimen, which was consisted of continuous infusion intermediate-dose cytarabine (1g/m(2)/day, 24h i.v. infusion x 5), mitoxantrone (12 mg/m(2)/day x 3), and etoposide (150 mg/m(2)/day x 3). We treated 33 patients and 17 (51.5%) achieved CR with a median duration of 117 days. Median overall survival was 219 days. Our results suggest that continuous infusion intermediate-dose cytarabine, together with mitoxantrone and etoposide, may induce CR in a significant proportion of patients with refractory or early relapsed AML, although remission duration was short.

Pazopanib for Non-small Cell Lung Cancer: The First Case Report in Korea.

Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors' knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer.

Randomized trial of postoperative adjuvant therapy in stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: a preliminary report.

PURPOSE: We conducted a prospective randomized trial to define the optimal sequence of chemotherapy and radiotherapy of postoperative adjuvant treatment in stage II and III rectal cancer. PATIENTS AND METHODS: Three hundred eight patients were enrolled onto the study. We randomly assigned 155 to arm I (early radiotherapy group) and 153 to arm II (late radiotherapy group). Treatment included eight cycles of chemotherapy at 4-week intervals and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on day 1 of the first chemotherapy cycle in arm I and on day 1 of the third chemotherapy cycle in arm II. The chemotherapy regimen consisted of fluorouracil 375 mg/m(2)/d and leucovorin 20 mg/m(2)/d. Chemotherapy was administered for 3 days per cycle in two cycles during the period of radiotherapy and for 5 days per cycle in the remaining six cycles. RESULTS: Twenty patients in arm I and 14 in arm II were not eligible. We included 274 patients in the analysis. With a median follow-up of 37 months for surviving patients, disease-free survival was significantly prolonged in arm I compared with arm II (81% v. 70% at 4 years; P =.043). Twenty-three recurrences occurred in arm I and 38 in arm II (P =.047). Overall survival was not significantly different between arms I and II (84% v. 82% at 4 years; P =.387). CONCLUSION: Early radiotherapy with concurrent chemotherapy after resection of stage II and III rectal cancer demonstrated a statistically significant advantage for disease-free survival compared with late radiotherapy with chemotherapy.

Prognostic factors identifiable at the time of onset of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

BACKGROUND AND OBJECTIVES: Current grading systems of acute graft-versus-host disease (GVHD) cannot effectively identify patients with poor prognosis at the onset of acute GVHD after allogeneic hematopoietic cell transplantation. DESIGN AND METHODS: In a retrospective analysis, we evaluated the prognostic value of various clinical parameters at the initiation of treatment in 83 patients who developed systemic treatment-requiring acute GVHD after allogeneic hematopoietic cell transplantation. RESULTS: Forty-three of 83 patients (52%) experienced initial treatment failure (40 required secondary treatment due to lack of response and 3 died) and 43 (52%) experienced treatment success, defined as completion of treatment (initial and, if given, secondary) within 100 days. The GVHD-specific survival rate was 65.5%, with 27 deaths due to GVHD-related complications without relapse of underlying malignancies within 1 year. HLA-mismatched transplantation, visceral initiation, and peripheral blood lymphocytopenia ( pound100/mL) were independent variables predicting higher initial treatment failure (Odd ratios (OR)=12.225, 12.036, and 7.481, respectively). The above variables and initial acute GVHD grade III-IV vs. II were independent variables predicting shorter GVHD-specific survival (OR=0.322, 0.247, 0.340, and 0.385, respectively). High-risk disease status, visceral initiation, and hypoalbuminemia ( pound2.8 g/dL) were independent variables predicting lower treatment success (OR=0.221, 0.162, and 0.270, respectively). The predictive value of visceral initiation and lymphocytopenia for GVHD-specific survival was verified in an independent cohort of 58 patients. INTERPRETATION AND CONCLUSIONS: Lymphocytopenia and hypoalbuminemia may be useful baseline prognostic factors for acute GVHD after allogeneic hematopoietic cell transplantation.

Docetaxel plus epirubicin as first-line chemotherapy in MBC (KCSG 01-10-05): phase II trial and the predictive values of circulating HER2 extracellular domain and vascular endothelial growth factor.

The anthracyclines and taxanes are considered to be the most active drugs in metastatic breast cancer (MBC). We conducted a multicenter phase II study to evaluate the efficacy and tolerability of the docetaxel plus epirubicin combination chemotherapy as first-line treatment in MBC and performed a prospective assessment of the predictive values of circulating HER2 extracellular domain (ECD) and vascular endothelial growth factor (VEGF). Docetaxel 75 mg/m(2) and epirubicin 75 mg/m(2) were given intravenously every 3 weeks. Prophylactic G-CSF was not used. Pretreatment serum HER2 ECD and VEGF levels were measured by enzyme immunoassay. Forty MBC patients were enrolled, and 39 patients were evaluable for toxicities and 38 for response. Complete response was observed in 3 (7.9%) patients, partial response in 20 (52.6%) (overall response rate 60.5%), stable disease in 11 (28.9%) and disease progression in 4 (10.5%). After a median follow-up of 22.5 months, the median duration of response was 28 weeks, median time to disease progression was 32 weeks, and median survival was 15.8 months. Two-hundred and fifteen cycles of treatment were administered (median, 6 cycles per patient). Grade 3 and 4 neutropenia were observed during 24 (11.2%) and 74 (35%) cycles respectively, and grade 3 or 4 febrile neutropenia in 24 (11.2%) cycles. Elevated circulating HER2 ECD levels were found to be associated with a shorter response duration (p<0.005) and shorter time to progression (p<0.005). However, elevated VEGF levels were not found to be correlated with response rate or survival. We concluded that the docetaxel and epirubicin combination is an effective first-line treatment in MBC patients and that elevated serum HER2 ECD levels, but not circulating VEGF levels, predict a poor outcome.

Prognostic significance of Fas (CD95) and TRAIL receptors (DR4/DR5) expression in acute myelogenous leukemia.

We analyzed the clinical significance of the expression of the Fas (CD95) and TNF-related apoptosis-inducing ligand (TRAIL) receptors, the death receptors (DR) 4 and 5, by leukemic blasts in 29 patients with acute myelogenous leukemia (AML). CD95 was positive in 18 patients (62%). The DR4 and DR5 receptors were positive in 20 patients (69%) and 29 (100%), respectively. CD95 positivity was not correlated with cytogenetic abnormalities. Complete remission (CR) rate was not significantly different according to the expression of the CD95 or TRAIL receptors. Relapse-free survival was significantly prolonged in patients with CD95-positive AML cells compared with patients with CD95-negative AML cells (73% versus 38% at 3 years; P = 0.047). TRAIL receptors did not show correlation with other clinical parameters.

Analysis of fatal intracranial hemorrhage in 792 acute leukemia patients.

Forty-one of 792 acute leukemia patients suffered fatal intracranial hemorrhage (FICH). Acute promyelocytic leukemia was the most common subtype. Achievement of complete remission in AML was significantly influenced by FICH. FICH accounts for about half of deaths from hemorrhage and this proportion has not changed despite improvements in leukemia management.

Collection of peripheral blood progenitor cells: analysis of factors predicting the yields.

We retrospectively analyzed data on 628 leukapheresis from 160 consecutive patients with hematologic or solid malignancies to identify predictive factors affecting the achievement of optimal peripheral blood progenitor cell (PBPC) collection, which was defined as > or = 5x10(6) CD34+ cells/kg. In univariate analysis, a diagnosis of multiple myeloma, no prior axial skeletal radiotherapy, absence of exposure to alkylating agents and cisplatin, fewer cycles of chemotherapy, and fewer number of previous chemotherapy regimens favored the achievement of target number of PBPC. In multivariate analysis, the absence of prior exposure to alkylating agents, especially cyclophosphamide, (P=0.003, RR=2.08) and cisplatin (P=0.015, RR=2.50) were independent predicting factors affecting the probability of achieving the target PBPC and the time to reach the target PBPC collection. In addition, the total dose of cyclophosphamide the patient received significantly alters the mobilization.

The efficacy of high-dose melphalan with autologous peripheral blood stem cell transplantation in patients with multiple myeloma.

Although high-dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) is widely accepted as an effective and safe consolidation therapy for multiple myeloma (MM), few reports on its efficacy are available in Korea. We present the results of a prospective phase II study, involving 33 patients with MM treated with HDT with ASCT. The treatment consisted of 4 courses of VAD (vincristine, adriamycin, dexamethasone) induction, peripheral blood stem cell collection, and high-dose melphalan with stem cell infusion. The overall response rate was 93%, with 45% of patients having complete responses. The toxicity was predictable and tolerable. With a median follow-up of 27.6 months, the 2-year event free survival rate was 43%. At the time of writing, the median overall survival duration had not been reached with 2-year survival and projected 3-year survival rates of 81% and 74%, respectively. The overall survival was significantly better than that of the historical control patients (N=82) treated with conventional chemotherapy at our institution. The results suggest that HDT with ASCT is a valuable first or second-line treatment for patients with MM.

Radiation recall dermatitis induced by tamoxifen during adjuvant breast cancer treatment.

Tamoxifen and radiotherapy are used in breast cancer treatment worldwide. Radiation recall dermatitis (RRD), induced by tamoxifen, has been rarely reported. Herein, we report a RRD case induced by tamoxifen. A 47-year-old woman had a right quadrantectomy and an axillary lymph node dissection due to breast cancer. The tumor was staged pT2N0; it was hormone receptor positive, and human epidermal growth factor receptor 2 negative. The patient received adjuvant chemotherapy followed by tamoxifen and radiotherapy. After 22 months of tamoxifen, the patient developed a localized heating sensation, tenderness, edema, and redness at the irradiated area of the right breast. The symptoms improved within 1 week without treatment. Three weeks later, however, the patient developed similar symptoms in the same area of the breast. She continued tamoxifen before and during dermatitis, and symptoms resolved within 1 week.

Small cell carcinoma of the liver and biliary tract without jaundice.

An 80-year-old woman presenting with chest pain was found to have a large, lobulated soft tissue mass in the liver and nearby tissues on abdominal computed tomography (CT). The tumor had invaded the common hepatic artery and main portal vein. Jaundice developed 4 wk later, at which point, a pancreas and biliary CT scan revealed a large mass in the right lobe of the liver and a hilar duct obstruction, which was found to be a small cell carcinoma. Despite its rarity, liver and bile duct small cell carcinoma should be considered in the differential diagnosis of atypical chest pain without jaundice.

Randomized trial of postoperative adjuvant therapy in Stage II and III rectal cancer to define the optimal sequence of chemotherapy and radiotherapy: 10-year follow-up.

PURPOSE: To determine the optimal sequence of postoperative adjuvant chemotherapy and radiotherapy in patients with Stage II or III rectal cancer. METHODS AND MATERIALS: A total of 308 patients were randomized to early (n = 155) or late (n = 153) radiotherapy (RT). Treatment included eight cycles of chemotherapy, consisting of fluorouracil 375 mg/m(2)/day and leucovorin 20 mg/m(2)/day, at 4-week intervals, and pelvic radiotherapy of 45 Gy in 25 fractions. Radiotherapy started on Day 1 of the first chemotherapy cycle in the early RT arm and on Day 1 of the third chemotherapy cycle in the late RT arm. RESULTS: At a median follow-up of 121 months for surviving patients, disease-free survival (DFS) at 10 years was not statistically significantly different between the early and late RT arms (71% vs. 63%; p = 0.162). A total of 36 patients (26.7%) in the early RT arm and 49 (35.3%) in the late RT arm experienced recurrence (p = 0.151). Overall survival did not differ significantly between the two treatment groups. However, in patients who underwent abdominoperineal resection, the DFS rate at 10 years was significantly greater in the early RT arm than in the late RT arm (63% vs. 40%; p = 0.043). CONCLUSIONS: After the long-term follow-up duration, this study failed to show a statistically significant DFS advantage for early radiotherapy with concurrent chemotherapy after resection of Stage II and III rectal cancer. Our results, however, suggest that if neoadjuvant chemoradiation is not given before surgery, then early postoperative chemoradiation should be considered for patients requiring an abdominoperineal resection.

Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation.

We investigated the occurrence of hepatic veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT) in 241 adults conditioned with busulfan + cyclophosphamide at a single institute and retrospectively compared 186 patients who received oral busulfan (O-Bu group) with 55 patients who received intravenous busulfan (I-Bu group). Various hemostatic parameters were determined at baseline and on days 0, 7, 14, and 21. Hepatic VOD occurred in 41.7% of the O-Bu group and in 18.5% of the I-Bu group. Multivariate analysis revealed that the I-Bu group had significantly decreased risk of VOD compared to the O-Bu group [p=0.006, odds ratio: (OR) 0.345]. Eleven patients in the O-Bu group and none of the I-Bu group developed severe VOD. A repeated measures analysis of variance (ANOVA) with a between-subjects factor revealed significant differences in post-transplant levels of antithrombin III, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and D-dimer according to the occurrence of VOD. The level of antithrombin III was significantly lower, whereas the level of D-dimer was significantly higher, in the O-Bu group than in the I-Bu group. These findings show that, in adults conditioned with busulfan + cyclophosphamide, intravenous busulfan was associated with significantly decreased incidence of VOD and fewer hemostatic derangements after allogeneic BMT compared to oral busulfan.

Double autologous stem cell transplantation for multiple myeloma: a Korean single center study.

BACKGROUND: Although high dose chemotherapy coupled with an autologous stem cell transplantation (ASCT) is widely accepted as effective therapy for multiple myeloma (MM), few reports are available in Korea, especially in the area of double ASCT. We present the results of an institutional retrospective study of 12 patients with MM treated by double ASCT. METHODS: Eligible patients received induction therapy using vincristine, adriamycin, dexamethasone (VAD), and mobilization was performed using cyclophosphamide plus lenograstim. High-dose melphalan (total 200 mg/m2) was used to condition the ASCT. RESULTS: The median interval from diagnosis to ASCT was 6 months (range, 1.8-15.3 months). The median interval between the 1st and 2nd ASCT was 4.4 months (range 2.1-48.7 months). The median follow up was 18.3 months (range 8.1-50.5 months) for the nine surviving patients. No therapy-related mortality occurred. Following induction chemotherapy, two patients experienced CR. Following double ASCT, eight patients experienced CR. The 5 year OS was 59%. The median duration of event free survival was 2.13 years (95% CI, 0.84-3.42). CONCLUSION: Although the results of study did not demonstrate the advantage of double ASCT, this is the first report to outline the outcome of double ASCT for Korean MM patients.

Hemorrhagic cystitis following allogeneic hematopoietic cell transplantation.

We conducted a retrospective study to investigate the incidence, risk factors, and clinical features of hemorrhagic cystitis (HC) following allogeneic hematopoietic cell transplantation (allo-HCT). Adult patients who developed HC after allo-HCT were identified from the HCT database of the Asan Medical Center and their medical records were reviewed. From December 1993 to August 2001, a total of 210 adult patients underwent allo-HCT. Fifty-one patients developed HC with a cumulative incidence of 25.7%. The median onset of HC was post-transplant day 24 (range, -2 to 474), and the median duration was 31 days (range, 8 to 369). Significant risk factors for HC by univariate analysis included diagnosis of chronic myelogenous leukemia (p=0.028), unrelated HCT (p=0.029), grade III-IV acute graft-versus-host disease (GVHD) (p<0.001), extensive chronic GVHD (p=0.001), and positive cytomegalovirus antigenemia between post transplant days 31 and 60 (p=0.031). Multivariate analysis showed that grade III-IV acute GVHD was the most important risk factor for the occurrence of HC after allo-HCT (odds ratio, 3.38; 95% CI, 1.36-8.39). Late-onset HC, which occurred beyond 3 weeks after allo-HCT, was more frequently associated with GVHD than early-onset HC (p=0.007). Our data suggest that a portion of late-onset HC might be a manifestation of GVHD.

Graft-versus-host disease (GVHD)-specific survival and duration of systemic immunosuppressive treatment in patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation.

We investigated graft-versus-host disease (GVHD)-specific survival (GSS) and the duration of systemic immunosuppressive treatment (IST) in 82 patients who developed chronic GVHD following allogeneic haematopoietic cell transplantation (HCT). These two major study endpoints were calculated using the Kaplan-Meier method. Deaths solely due to the relapse of underlying disease or accidental deaths were censored at the time of occurrence for the analysis of GSS. The probability of GSS at 5 years was 74.2%. The median duration of systemic IST for chronic GVHD was 272 d (range: 7-1450), and the probability of withdrawal of systemic IST at 1, 2 and 3 years was 67.3%, 82.4% and 89.0% respectively. Analysis based on a multivariate model showed that a diagnosis other than leukaemia or myelodysplastic syndrome (P = 0.049), prior occurrence of grade III-IV acute GVHD (P = 0.021), onset of chronic GVHD before d 120 (P = 0.013), serum alkaline phosphatase over 120 IU/l (P = 0.034), and serum bilirubin over 34.2 micromol/l (P = 0.015) were independent adverse prognostic factors for GSS. Prior occurrence of grade III-IV acute GVHD significantly influenced the duration of systemic IST (P = 0.048). In conclusion, analyses of GSS and the duration of systemic IST will allow patients with different outcomes to be stratified for appropriate treatment application and will provide important parameters in prospective trials for the treatment of chronic GVHD.

Changes of isoagglutinin titres after ABO-incompatible allogeneic stem cell transplantation.

We investigated the changes in isoagglutinin titres in 62 patients who underwent ABO-incompatible allogeneic stem cell transplantation. After major [and/or (+/-) minor] ABO-incompatible transplantation, recipient-derived isoagglutinins against donor-type red blood cells (RBCs) disappeared more rapidly in unrelated recipients (P = 0.006) and in patients with acute graft-versus-host disease (GVHD, P = 0.025) than in sibling recipients and in patients without acute GVHD respectively. Pure red cell aplasia (PRCA) developed in 10 out of 35 evaluable patients who underwent major (+/- minor) ABO-incompatible transplantation, and the post-transplant increase of isoagglutinin titres was a significant predictor for the occurrence of PRCA. In five out of 36 patients who underwent minor (and/or (+/-) major) ABO-incompatible transplantation, donor-derived isoagglutinins against recipient RBCs were detectable without clinically overt haemolysis. Isoagglutinin titres against ABO antigens absent both on recipient and donor RBCs decreased during the early post-transplant period then rose subsequently in 24 out of 29 patients at (median) d 59 post transplant. Our study showed that changes in isoagglutinin titres might have clinical implications in the occurrence of immunohaematological complications such as PRCA or immune-mediated haemolysis, and might reflect immunohaematological reconstitution after transplantation. Furthermore, our data regarding time to disappearance of recipient-derived isoagglutinins against donor-type RBCs after major ABO-incompatible transplantation suggest the presence of a graft-versus-plasma cell effect.

Clinical usefulness of the hematopoietic progenitor cell counts in predicting the optimal timing of peripheral blood stem cell harvest.

Although enumeration of CD34+ cells in the peripheral blood (PB) on the day of apheresis predicts the quantity of those cells collected, the flow cytometric techniques used are complex and expensive, and several hours are required to obtain the result in the clinical practice setting. The Sysmex SE-9000 automated haematology analyzer provides an estimate of immature cells, called hematopoietic progenitor cells (HPC). The aim of this study was to evaluate the clinical usefulness of HPC in predicting the optimal timing of peripheral blood progenitor cells (PBPC) harvest. Studies were performed on 628 aphereses from 160 patients with hematologic or solid malignancies. Spearman's rank statistics was used to assess correlation between HPC, WBC, mononuclear cells (MNC), and CD34+ cells. A receiver operating characteristic (ROC) curve was drawn for cutoff value of HPC, and predictive values of the chosen cutoff value of HPC for different target CD34+ cell collections were calculated. The PB HPC had a stronger correlation (rho=0.592, p<0.001) with collected CD34+ cells than did PB WBC and PB MNC. The ROC curve showed that the best cutoff value of HPC was 50 x 10(6)/L for the target CD34+ cells > or =1 x 10(6)/kg with sensitivity of 75%. Positive and negative predictive values of HPC > or =50 x 10(6)/L for CD34+ cells > or =1 x 10(6)/kg were 59.7% and 81.1%, respectively. In the clinical practice setting, applying variable cutoff values of HPC would be a useful tool to predict the optimal timing of PBPC collection.

Efficacy of neoadjuvant chemoradiotherapy in resectable esophageal squamous cell carcinoma--a single institutional study.

A prospective phase II study of neoadjuvant chemoradiotherapy (CRT) for resectable esophageal squamous cell carcinoma was conducted from May 1993 to March 1996. A total of 88 patients fitted the eligibility criteria and were treated with two courses of induction chemotherapy (cisplatin 60 mg/m2/day on day 1 and 5-fluorouracil (5-FU) 1000 mg/m2/day on days 2-6) with concurrent hyperfractionated radiotherapy (48 Gy/40 fractions/4 weeks) followed by esophagectomy or definitive CRT comprising 4 cycles of cisplatin/5-FU and hyperfractionated radiotherapy (additional 12 Gy) with intracavitary brachytherapy (9 Gy). Clinical response and downstaging were achieved in 83% and 42% of the patients, respectively. With a median follow-up of 77 months, median survival time was 18 months with a 5-year survival rate of 23%. The clinical responses to CRT and surgery were independent prognostic factors for overall survival. Among the intended surgery group (n = 52), 41 (79%) patients underwent surgery and 36 had a resection with a pathologic complete response rate of 43%. When compared with a matched historical control (n = 40), there was a significant survival benefit in the multimodality arm (p = 0.04). This multimodality therapy was feasible and its efficacy was promising, especially when surgical resection was performed. The therapeutic benefit of neoadjuvant CRT remains to be assessed in large well-designed randomized trials, one of which is ongoing at our institution.

The prophylactic use of lamivudine can maintain dose-intensity of adriamycin in hepatitis-B surface antigen (HBs Ag)-positive patients with Non-Hodgkin's lymphoma who receive cytotoxic chemotherapy.

We investigated the effectiveness of lamivudine to prevent hepatitis flare up due to reactivation of hepatitis-B virus (HBV) in hepatitis-B surface antigen (HBsAg)-positive patients with Non-Hodgkin's lymphoma (NHL) during cytotoxic chemotherapy. HBsAg-positive patients with NHL were identified from the lymphoma database of the Asan Medical Center from January 1995 to August 2002, and their medical records were reviewed. We found that 31 patients were received cytotoxic chemotherapy among 41 NHL patients with HBsAg-positive during same period. We divided them into 2 groups of HBsAg patients with NHL as follows: Group A who received cytotoxic chemotherapy with lamivudine 100 mg daily; Group B without any prophylactic antiviral therapy. There were no significant differences between Group A and B in several clinical variables. Seventeen patients (85%) in group B and one patient (9%) in Group A had hepatitis due to reactivation of HBV (p<0.001), with one hepatic failure related death in Group B and none in group A. The mean dose intensity of adriamycin actually delivered was 13.3 mg/m2/week (80% Relative Dose intensity (RDI)) in Group A and 9.1 mg/m2/week (55% RDI) in Groups B (p<0.001). Our data suggest that the frequency of chemotherapy-related HBV reactivation may be significantly decreased by lamivudine prophylaxis with maintenance of the dosage of adriamycin.