Tsu Yi Chao

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

PURPOSEnThe results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status.nnnPATIENTS AND METHODSnIn all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS.nnnRESULTSnOS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09).nnnCONCLUSIONnEGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial

BACKGROUNDnAfatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.nnnMETHODSnIn this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136.nnnFINDINGSnBetween May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group.nnnINTERPRETATIONnAlthough we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment.nnnFUNDINGnBoehringer Ingelheim Inc.

A revisit of prophylactic lamivudine for chemotherapy‐associated hepatitis B reactivation in non‐Hodgkin's lymphoma: A randomized trial

Lamivudine is effective to control hepatitis B virus (HBV) reactivation in HBV‐carrying cancer patients who undergo chemotherapy, but the optimal treatment protocol remains undetermined. In this study, HBV carriers with newly diagnosed non‐Hodgkins lymphoma (NHL) who underwent chemotherapy were randomized to either prophylactic (P) or therapeutic (T) lamivudine treatment groups. Group P patients started lamivudine from day 1 of the first course of chemotherapy and continued treatment until 2 months after completion of chemotherapy. Group T patients received chemotherapy alone and started lamivudine treatment only if serum alanine aminotransferase (ALT) levels elevated to greater than 1.5‐fold of the upper normal limit (ULN). The primary endpoint was incidence of HBV reactivation during the 12 months after starting chemotherapy. During chemotherapy, fewer group P patients had HBV reactivation (11.5% versus 56%, P = 0.001), HBV‐related hepatitis (7.7% versus 48%, P = 0.001), or severe hepatitis (ALT more than 10‐fold ULN) (0 versus 36%, P < 0.001). No hepatitis‐related deaths occurred during protocol treatment. Prophylactic lamivudine use was the only independent predictor of HBV reactivation. After completion of chemotherapy, the incidence of HBV reactivation did not differ between the 2 groups. Two patients, both in group P, died of HBV reactivation–related hepatitis, 173 and 182 days, respectively, after completion of protocol treatment. When compared with an equivalent group of lamivudine‐naïve lymphoma patients who underwent chemotherapy, therapeutic use of lamivudine neither reduced the severity of HBV‐related hepatitis nor changed the patterns of HBV reactivation. Conclusion: Prophylactic lamivudine use, but not therapeutic use, reduces the incidence and severity of chemotherapy‐related HBV reactivation in NHL patients. (HEPATOLOGY 2008;47:844–853.)

Hepatocellular carcinoma with intra-atrial tumor thrombi. A report of three cases responsive to thalidomide treatment and literature review.

Background: In patients with advanced hepatocellular carcinoma (HCC), inferior vena cava/intra-right atrial (IVC/RA) tumor thrombi are not uncommon findings and are usually associated with extremely poor outcome. Surgical interventions as well as nonsurgical approaches, such as transcatheter arterial chemoembolization and radiotherapy, have been used in the treatment of patients with symptomatic IVC/RA tumor thrombi. However, such therapeutic modalities are usually not feasible when a patient shows poor general performance, the presence of metastatic disease, and underlying hepatic dysfunction. Such patients show limited survival. Material and Methods: Herein we describe 3 patients with advanced-stage HCC whose IVC/RA tumor thrombi and primary tumors regressed remarkably after low-dose thalidomide (200–400 mg/day) therapy. An Entrez PUBMED search of English Literature articles was performed to identify other cases of RA tumor thrombi in HCC who had received various treatments. Results: Two of our patients survived for more than 15 months after the diagnosis of IVC/RA tumor thrombi, while the other had effective symptomatic palliation associated with a drastic fall of AFP serum levels and significant tumor regression within 4 weeks of thalidomide therapy. A literature review suggested that the survival of our patients is comparable with that of occasional patients who had received aggressive surgical intervention. Conclusions: Our results suggest that, despite the low tumor response rate in earlier studies, thalidomide therapy may sometimes provide effective palliation for patients with far advanced HCC with symptomatic IVC/RA tumor thrombi and who are not candidates for alternative treatment options.

Adrenal insufficiency caused by primary aggressive non-Hodgkin's lymphoma of bilateral adrenal glands: report of a case and literature review

Abstractu2002A 64-year-old woman was hospitalized because of poor general condition, gastrointestinal upset, unexplained fever, electrolyte imbalances, and an incidental finding of bilateral huge adrenal masses on computerized tomography (CT) of the abdomen. Non-Hodgkins lymphoma (NHL) of B-cell origin was proven by ultrasound-guided aspiration biopsy of the left adrenal gland. Meanwhile, primary adrenal insufficiency was confirmed by her low serum cortisol level, high ACTH level, and inadequate adrenal response to the rapid ACTH stimulation test. The diagnosis of primary adrenal NHL was supported by detailed physical examinations, bone marrow examination, and such imaging studies as CT scan and sonography. She received three courses of chemotherapy with cyclophosphamide, vincristine, and prednisolone and there was an initial transient response, but she died of sepsis and progression of NHL three and a half months later.

Chamaecypanone C, a novel skeleton microtubule inhibitor, with anticancer activity by trigger caspase 8-Fas/FasL dependent apoptotic pathway in human cancer cells

Microtubule is a popular target for anticancer drugs. Chamaecypanone C, is a natural occurring novel skeleton compound isolated from the heartwood of Chamaecyparis obtusa var. formosana. The present study demonstrates that chamaecypanone C induced mitotic arrest through binding to the colchicine-binding site of tubulin, thus preventing tubulin polymerization. In addition, cytotoxic activity of chamaecypanone C in a variety of human tumor cell lines has been ascertained, with IC(50) values in nanomolar ranges. Flow cytometric analysis revealed that chamaecypanone C treated human KB cancer cells were arrested in G(2)-M phases in a time-dependent manner before cell death occurred. Additional studies indicated that the effect of Chamaecypanone C on cell cycle arrest was associated with an increase in cyclin B1 levels and a mobility shift of Cdc2/Cdc25C. The changes in Cdc2 and Cdc25C coincided with the appearance of phosphoepitopes recognized by a marker of mitosis, MPM-2. Interestingly, this compound induced apoptotic cell death through caspase 8-Fas/FasL dependent pathway, instead of mitochondria/caspase 9-dependent pathway. Notably, several KB-derived multidrug resistant cancer cell lines overexpressing P-gp170/MDR and MRP were sensitive to Chamaecypanone C. Taken together, these findings indicated that Chamaecypanone C is a promising anticancer compound that has potential for management of various malignancies, particularly for patients with drug resistance.

A Randomized, Double-blind, Parallel, Comparative Study to Evaluate the Efficacy and Safety of Ramosetron plus Dexamethasone Injection for the Prevention of Acute Chemotherapy-induced Nausea and Vomiting

OBJECTIVEnTo evaluate the efficacy of intravenous ramosetron plus dexamethasone for the prevention of acute chemotherapy-induced nausea and vomiting.nnnMETHODSnCancer patients scheduled to receive chemotherapy containing either of the four drugs (cisplatin, doxorubicin, epirubicin or oxaliplatin) were enrolled. They were randomized to receive intravenous ramosetron 0.3 mg plus dexamethasone 20 mg or granisetron 3 mg plus dexamethasone 20 mg 30 min before chemotherapy on day 1. The primary efficacy parameter is complete response rate, which was defined by the proportion of patients without vomiting and no requirement for rescue drugs within 24 h after chemotherapy.nnnRESULTSnA total of 285 patients were enrolled. The primary efficacy analysis included 274 patients. The complete response rate was 77.37% in the ramosetron 0.3 mg plus dexamethasone 20 mg group (137 patients) and 81.75% in the granisetron 3 mg plus dexamethasone 20 mg group (137 patients) with a difference of -4.38% (95% confidence interval: -14.64, 5.89). Therefore, non-inferiority of ramosetron 0.3 mg plus dexamethasone 20 mg to granisetron 3 mg plus dexamethasone 20 mg was demonstrated with non-inferiority margin -15%. For patients treated with cisplatin, non-inferiority of ramosetron 0.3 mg plus dexamethasone 20 mg to granisetron 3 mg plus dexamethasone 20 mg could not be demonstrated. Only a few patients required rescue medications, 7.3% in the ramosetron 0.3 mg plus dexamethasone 20 mg group and 5.1% in the granisetron 3 mg plus dexamethasone 20 mg group (P = 0.44). All 285 patients were included for safety analysis; 36.11% (52/144) and 23.40% (33/141) experienced at least one adverse event within 24 h in the ramosetron 0.3 mg plus dexamethasone 20 mg and granisetron 3 mg plus dexamethasone 20 mg groups, respectively. Four ramosetron-related adverse events among 144 patients were observed including two moderate elevation of liver enzymes and one each of mild hiccup and moderate skin rash.nnnCONCLUSIONSnThe combination of ramosetron plus dexamethasone was an effective treatment to prevent acute chemotherapy-induced nausea and vomiting.

Randomized Phase II Trial of Thalidomide Alone versus Thalidomide Plus Interferon Alpha in Patients with Refractory Multiple Myeloma

The potential synergistic anti-myeloma effect for thalidomide combining with interferon alpha was not yet clear clinically. From March 2001 to January 2004, a total of 28 heavily pretreated multiple myleoma (MM) patients were enrolled in this open-labeled, randomized Phase II study. Patients with refractory MM were randomized to receive either thalidomide alone (200 mg/day up to the maximum dose 800 mg/day, arm B) or the combination of thalidomide and interferon alpha (3 MIU/m2 subcutaneous injection 3 times weekly, arm A). The objective of this study was to compare the safety and efficacy of thalidomide alone to combined regimen. The patients characteristics were similar between the 2 arms. However, the average treatment duration was significantly longer in the arm B than the arm A (236 days versus 101 days, p = 0.029). Serum levels of paraprotein decline ≥ 25 percent were obtained in 6 of 12 patients (50.0 percent) treated with arm B and 3 of the 16 patients (18.8 percent) treated with arm A. The estimated time to event was 7.9 months (95 percent confidence interval [95%CI], 0.5–15.4) for arm B and 1.5 months (95%CI, 0.0–3.4) for arm A (log-rank test, p = 0.0193). The major adverse events in both arms consisted of neutropenia, anemia, thrombocytopenia, constipation, somnolence, and skin rash. Our study showed that thalidomide alone was effective and tolerated in patients with relapsed or refractory MM. The thalidomide combined with interferon alpha resulted in a lower frequency of paraprotein response, shorter treatment-duration and 25 percent of patients refusing rate. It may be concluded that the combined regimen is not well tolerated in our patients and needed to be further evaluated in the future.

Non-Hodgkin's Lymphoma of the Stomach: Treatment Outcomes for 57 Patients Over a 20-Year Period

Background: Gastric non‐Hodgkins lymphoma (NHL) is a rare subtype of malignancy, for which no consensus exists about treatment. In this study, the treatment outcomes of gastric NHL in 57 patients were retrospectively evaluated for a period of 20 years at a single institute. Methods: Clinical stages were classified according to the Ann Arbor staging system: 29 patients were stage I, 17 stage II, two stage III, and nine stage IV. The 46 stage I/II patients received aggressive, multimodal therapy: 24 of these (group A) were treated with surgery‐based management, which included surgery alone (n = 6), surgery + chemotherapy (CT; n = 14), surgery + radiotherapy (RT; n = 2), and surgery + CT + RT (n = 2); 22 patients (group B) did not receive surgery, but received CT alone (n = 11), CT + RT (n = 5), or, in patients with low‐grade mucosa‐associated lymphoid tissue (MALT) lymphoma, an oral anti‐Helicobacter pylori regimen (n = 6). The 11 stage III/IV patients received CT and/or RT with regimens similar to those for stage I/II patients. Results: Except for 1 patient with an initial surgical diagnosis, 56 patients underwent gastric endoscopic examination, which proved that 42 had NHL. The rate of diagnostic accuracy by gastroscopy was 75%. After multimodal treatment (n = 46) and a median follow‐up of 54 months (range, 1–210 months), the 5‐year survival rate was 40.3%. The 5‐year survival rates for stage I, II and III/IV patients were 57.2%, 47% and 0%, respectively (p < 0.005). Of the 24 surgical patients (group A) who received sequential CT, with or without RT, 12 remained disease‐free after a median follow‐up of 98 months (range, 1–210 months); 3 patients died because of postoperative complications. Of the 22 non‐surgical patients (group B) who received CT, alone or combined with RT, 14 remained disease‐free after a median follow‐up of 40 months (range, 4–189 months); 1 patient died because of massive gastric hemorrhage after CT. All stage III and IV patients died after a median survival of 4 months (range, 1–8 months). Conclusion: Clinical stage is the most important factor predicting the long‐term survival of patients with gastric NHL. Surgery may still be necessary in cases of failed gastroscopic diagnosis. In early‐stage gastric NHL, non‐surgical treatment seems able to achieve the aims of improved long‐term survival and, in some instances, cure.

Phase II study of oxaliplatin in combination with continuous infusion of 5-fluorouracil/leucovorin as first-line chemotherapy in patients with advanced gastric cancer

This study was designed to determine the efficacy and safety of biweekly oxaliplatin in combination with infusional 5-fluouracil (5-FU) and leucovorin in patients with advanced gastric cancer (AGC). Fifty-five eligible patients with measurable or assessable M/AGC (median age 62 and 90% of patients presented with metastasis) received oxaliplatin (85u2009mg/m2) intravenous infusion for 2u2009h, followed by intravenous infusion of 5-FU (3000u2009mg/m2) and leucovorin (100u2009mg/m2) for 46u2009h every 14 days until the patients disease was either in progression, unacceptable toxicity, patients withdrawal or the investigators decision to discontinue treatment. Of the 55 enrolled patients, 48 were evaluable for response. Three patients (5.4%) showed complete remission and 20 patients (36.4%) achieved partial response. The overall response rate was 47.9%. Nineteen patients (34.5%) had stable disease and six patients (10.9%) showed progressive disease. The median time to progression was 5.6 months and the median overall survival was 10.8 months. Grade 3/4 toxicities included leucopenia (12.7%), thrombocytopenia (5.4%), diarrhoea (3.6%) and vomiting (9.1%). Peripheral neuropathy was noted in 61.8% of the patients (grade 1/2: 54.5%; grade 3: 7.3%). Our study confirmed that the combination of oxaliplatin and continuous infusion of 5-FU/leucoverin without bolus 5-FU as first-line chemotherapy is active for patients with AGC and relatively safe with lower haematological toxicity.