Changhoon Yoo

A randomised phase II study of modified FOLFIRI.3 vs modified FOLFOX as second-line therapy in patients with gemcitabine-refractory advanced pancreatic cancer.

Background:Only a few clinical trials have been conducted in patients with advanced pancreatic cancer after failure of first-line gemcitabine-based chemotherapy. Therefore, there is no current consensus on the treatment of these patients. We conducted a randomised phase II study of the modified FOLFIRI.3 (mFOLFIRI.3; a regimen combining 5-fluorouracil (5-FU), folinic acid, and irinotecan) and modified FOLFOX (mFOLFOX; a regimen combining folinic acid, 5-FU, and oxaliplatin) regimens as second-line treatments in patients with gemcitabine-refractory pancreatic cancer.Methods:The primary end point was the 6-month overall survival rate. The mFOlFIRI.3 regimen consisted of irinotecan (70 mg m−2; days 1 and 3), leucovorin (400 mg m−2; day 1), and 5-FU (2000 mg m−2; days 1 and 2) every 2 weeks. The mFOLFOX regimen was composed of oxaliplatin (85 mg m−2; day 1), leucovorin (400 mg m−2; day 1), and 5-FU (2000 mg m−2; days 1 and 2) every 2 weeks.Results:Sixty-one patients were randomised to mFOLFIRI.3 (n=31) or mFOLFOX (n=30) regimen. The six-month survival rates were 27% (95% confidence interval (CI)=13–46%) and 30% (95% CI=15–49%), respectively. The median overall survival periods were 16.6 and 14.9 weeks, respectively. Disease control was achieved in 23% (95% CI=10–42%) and 17% patients (95% CI=6–35%), respectively. The number of patients with at least one grade 3/4 toxicity was identical (11 patients, 38%) in both groups: neutropenia (7 patients under mFOLFIRI.3 regimen vs 6 patients under mFOLFOX regimen), asthaenia (1 vs 4), vomiting (3 in both), diarrhoea (2 vs 0), and mucositis (1 vs 2).Conclusion:Both mFOLFIRI.3 and mFOLFOX regimens were tolerated with manageable toxicity, offering modest activities as second-line treatments for patients with advanced pancreatic cancer, previously treated with gemcitabine.

Resumption of imatinib to control metastatic or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib (RIGHT): a randomised, placebo-controlled, phase 3 trial

BACKGROUND Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients. METHODS In our prospective, randomised, double-blind trial, we enrolled adults (≥18 years) who had previously benefited from first-line imatinib (initial response or stable disease for ≥6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1:1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug. FINDINGS Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5·2 months (IQR 3·4-9·4), median PFS was 1·8 months (95% CI 1·7-3·6) with imatinib compared with 0·9 months (0·9-1·7) with placebo (hazard ratio for progression or death 0·46, 95% CI 0·27-0·78; p=0·005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]). INTERPRETATION In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression.

The Efficacy and Safety of Sunitinib in Korean Patients with Advanced Renal Cell Carcinoma: High Incidence of Toxicity Leads to Frequent Dose Reduction

OBJECTIVE The effects of sunitinib in a broad patient population, especially those of Asian ethnicity, have been rarely investigated. Here, we assessed the efficacy and safety of sunitinib in Korean patients with advanced renal cell carcinoma. METHODS Between April 2006 and August 2008, 77 Korean patients with advanced renal cell carcinoma were treated with sunitinib. We performed retrospective analysis for efficacy in terms of survival outcomes and response rate. Toxicity profiles were also assessed. RESULTS A total of 65 patients, including 39 (60%) patients without previous cytotoxic or immunotherapy, were eligible for the analysis. In 53 patients with measurable lesions, the objective response rate was 43% and disease control was achieved in 46 (86%) patients. The median time to treatment failure, time to progression and overall survival were 7.0, 11.8 and 22.8 months, respectively, with a median follow-up of 26.8 months in surviving patients. The most common treatment-related adverse events were fatigue (81%) and stomatitis (60%). The most common Grade 3 or 4 adverse events were hand-foot syndrome (16%), thrombocytopenia (16%) and stomatitis (10%). Dose reduction was required in 46% of patients. CONCLUSIONS The efficacy was similar to a previous Phase III trial and a safety profile of sunitinib was manageable in Korean patients with advanced renal cell carcinoma, although the incidence of dose reduction and Grade 3 or 4 adverse events were higher than those of western reports. Future studies should investigate the ethnic differences in toxicity profiles of sunitinib.

Cross-Sectional Study of Imatinib Plasma Trough Levels in Patients With Advanced Gastrointestinal Stromal Tumors: Impact of Gastrointestinal Resection on Exposure to Imatinib

PURPOSE Imatinib plasma trough levels (C(min)) have been reported to correlate with treatment outcomes in patients with gastrointestinal stromal tumors (GISTs). We therefore have evaluated the correlation between imatinib C(min) and the clinical characteristics of patients with GIST. PATIENTS AND METHODS Steady-state imatinib C(min) in 107 patients with GIST who were taking imatinib 300 to 800 mg/d was measured. RESULTS In patients treated with imatinib 400 (n = 92), 300 (n = 7), 600 (n = 2), or 800 (n = 11) mg/d, imatinib C(min) was 1,305 +/- 633 ng/mL, 1,452 +/- 830 ng/mL, 1,698 +/- 725 ng/mL, and 3,330 +/- 1,592 ng/mL, respectively. Of the 92 patients treated with 400 mg/d imatinib, 59 patients (63%) were men; the median age was 55 years (range, 28 to 76 years), and the median duration of imatinib use before sampling was 8.8 months (range, 0.5 to 67.6 months). The mean inter- and intrapatient variability rates were 44.7% and 26.5%, respectively. In univariate analyses, high C(min) was correlated with advanced age (P = .02), low creatinine clearance (P = .001), low hemoglobin (P = .03), and low albumin (P < .001) concentrations. Imatinib C(min) was also significantly lower in patients with (n = 18; 942 +/- 330 ng/mL) than without (n = 74; 1,393 +/- 659 ng/mL) major (ie, total or subtotal) gastrectomy (P = .002). In multivariate analysis, albumin (P = .001) concentrations, creatinine clearance (P = .002), and major gastrectomy (P = .003) were significantly correlated with C(min). CONCLUSION In patients with GIST, imatinib C(min) at steady state was significantly associated with albumin concentration, creatinine clearance, and previous major gastrectomy. Although its clinical impact is unclear at present time, monitoring of imatinib C(min) might be particularly important for optimal treatment with imatinib in patients who have undergone major gastrectomy.

Limited role of interim PET/CT in patients with diffuse large B-cell lymphoma treated with R-CHOP.

Positron emission tomography (PET) has been found useful in monitoring response to treatment of malignant lymphoma. We investigated the ability of interim PET to monitor response to standard dose R-CHOP chemotherapy in chemotherapy-naïve patients with diffuse large B-cell lymphoma (DLBCL). Between March 2004 and April 2009, 155 DLBCL patients treated with R-CHOP and available for interim and post-treatment PET/CT were identified and included in this analysis. Response, progression-free survival (PFS), and overall survival (OS) were compared between interim PET/CT-negative and positive group, and among three patient groups which were categorized based on their interim and post-treatment PET/CT: those with early metabolic complete response (mCR), delayed mCR, and never mCR. Interim PET/CT-negative patients (n = 100) showed superior CR rates to interim PET/CT-positive patients (n = 55; 93% vs 62%, P < 0.001). However, there was no difference in PFS (P = 0.07) and OS (P = 0.24) between interim PET/CT-negative and positive group. We categorized patients into three groups, with 100 (64%) in the early mCR group, 35 (23%) in the delayed mCR group, and 20 (13%) in the never mCR group. Early mCR and delayed mCR group did not differ significantly in PFS (P = 0.84) or OS (P = 0.20). However, the survival outcome in the never mCR group was significantly inferior to the combined early and delayed mCR group. The result from this study suggests that interim PET/CT might be an inappropriate tool for designing risk-adaptive therapy in chemotherapy-naïve DLBCL patients treated with R-CHOP. Prospective trials should be performed to clearly determine the role of interim PET/CT.

Multicenter phase II study of trastuzumab in combination with capecitabine and oxaliplatin for advanced gastric cancer.

BACKGROUND Trastuzumab has been approved for use in combination with fluoropyrimidine plus cisplatin for the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). Although capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for AGC, combination trastuzumab plus XELOX has not been studied. METHODS Patients with metastatic or unresectable HER2-positive AGC were diagnosed by either HER2 immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in-situ hybridisation (FISH)+ received intravenous trastuzumab (8mg/m(2) for first cycle and 6mg/m(2) for subsequent cycles on day 1) plus oral capecitabine (1000mg/m(2) twice daily on days 1-14) and intravenous oxaliplatin (130mg/m(2) on day 1), every 3 weeks. The primary end-point was the objective response rate, and secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity profiles. RESULTS Fifty-five HER2-positive AGC patients were enrolled between August 2011 and February 2013. The median age was 57years (range=29-74). The confirmed objective response rate was 67% (95% confidence interval (CI)=54-80%). After a median follow-up period of 13.8 months (range=6.1-23.9), the median PFS and OS were 9.8 months (95% CI=7.0-12.6) and 21.0 months (95% CI=6.4-35.7), respectively. Frequently encountered grade 3-4 toxicities included neutropenia (18%), anaemia (11%), and peripheral neuropathy (11%). There was a treatment-related death caused by severe diarrhoea and complicated sepsis. CONCLUSION Combination of trastuzumab and XELOX is well tolerated and highly effective in patients with HER2-positive AGC.

Salvage Esophagectomy for Locoregional Failure After Chemoradiotherapy in Patients With Advanced Esophageal Cancer

BACKGROUND Definitive chemoradiotherapy is associated with high local treatment failure rates, and surgical resection may be an appropriate salvage therapy. However, the efficacy and safety of salvage esophagectomy have not been elucidated fully. The clinical outcomes of salvage esophagectomy for locoregional failure after chemoradiotherapy were assessed. METHODS Twelve patients who underwent salvage esophagectomy after chemoradiotherapy between January 2003 and November 2010 were included in this retrospective analysis. Baseline demographics and survivals of these patients were compared with 21 patients who did not receive salvage esophagectomy for locoregional failure only after chemoradiotherapy, identified from our own previous prospective trials. RESULTS The median age was 62.5 years (range 50 to 69) and all patients had squamous cell carcinoma. The median radiation dose was 54.0 Gy (range 41.4 to 66.0) and the median interval between completion of chemoradiation and surgery was 8.0 months (range 2.0 to 32.9). There were no in-hospital deaths. Pulmonary complication was the most common postoperative morbidity (42%), and anastomotic leakage occurred in 1 patient (8%). With a median follow-up period of 29.3 months (range 5.8 to 73.0), the overall 3-year survival rate was 58%. Patients with early pathologic stage disease (T1/2 and N0) showed significantly prolonged survival (p=0.03) compared with those with advanced pathologic stage (T3/T4 or N1). Patients with salvage esophagectomy had prolonged event-free survival and overall survival compared with those patients with locoregional failure who received primary chemotherapy or boost radiotherapy (p<0.001). CONCLUSIONS While salvage esophagectomy for locoregional failure after chemoradiotherapy should be employed with great caution, it appears to be a feasible and effective therapeutic option for highly selected patients, especially with early pathologic stage disease. Salvage esophagectomy can be recommended as the only current curative treatment option for patients with locoregional failure after chemoradiotherapy.

Impact of Immunohistochemistry-Based Molecular Subtype on Chemosensitivity and Survival in Patients with Breast Cancer Following Neoadjuvant Chemotherapy

Purpose Pathologic complete response (pCR) has been suggested as a surrogate prognostic indicator in breast cancer patients treated with neoadjuvant chemotherapy. We assessed whether the likelihood of pCR and survival is associated with the immunohistochemistry-based molecular subtypes. Methods We retrospectively analyzed the records of 276 patients with breast cancer who received neoadjuvant chemotherapy between January 2000 and January 2010. Patients were classified into four molecular subtypes based on the immunohistochemistry profiles of estrogen receptor, progesterone receptor, and HER2/neu. Logistic regression was used to analyze variables associated with pCR. Results The pCR was achieved in 45 patients (16.3%). The triple negative subtype was an independent predictive factor for pCR (odds ratio, 3.21; 95% confidence interval, 1.20-8.56; p=0.020), and the ERBB-2 subtype showed a trend for higher pCR rates (odds ratio, 3.03; 95% confidence interval, 0.93-9.89; p=0.067) compared with the luminal A subtype. In 99 patients with HER2/neu-positive breast cancer, pCR rates were higher in those who received trastuzumab (31.7%) than those treated with conventional chemotherapy regimens (17.2%, p=0.023). The pCR was significantly associated with prolonged progression-free survival (p=0.008). The triple negative subgroup had shorter progression-free survival (p=0.001) and overall survival (p=0.001) than the other subgroups. Conclusion We demonstrated that the triple negative and ERBB-2 subtypes are more likely to obtain pCR when neoadjuvant chemotherapy is given, compared to the luminal A subtype. Despite the high pCR rate, the triple negative subtype showed worse survival outcomes, paradoxically, primarily due to patients who had residual disease.

Serum beta-2 microglobulin in malignant lymphomas: an old but powerful prognostic factor.

Beta-2 microglobulin is synthesized in all nucleated cells and forms the light chain subunit of the major histocompatibility complex class I antigen. Despite its potential role as a convenient and non-invasive prognostic indicator in malignant lymphomas, the influence of serum β2 microglobulin is currently underestimated, and therapeutic decision making is rarely affected by this marker. Recent studies that included relatively large numbers of patients with specific histologic subtypes showed that serum β2 microglobulin is a potent prognostic marker in malignant lymphomas. In follicular lymphoma, this effort led to the incorporation of serum β2 microglobulin as an indicator in a new prognostic model. In this review, we summarize the current evidence supporting the role of serum β2 microglobulin as a prognostic factor in patients with malignant lymphoma and discuss perspectives for future investigations.

BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: A single center comparative analysis of efficacy and toxicity

We compared the efficacy and toxicity of BEAM (BCNU, etoposide, cytarabine and melphalan) and BuCyE (busulfan, cyclophosphamide and etoposide), given prior to autologous stem cell transplantation (ASCT), in 65 patients with non-Hodgkins lymphoma. Of these 65 patients, 43 received BEAM and 22 received BuCyE. Their age, gender distribution, International Prognostic Index, status of disease at ASCT and median number of infused CD34(+) cells/kg were similar. Neutrophil and platelet engraftment were significantly faster in the BuCyE group. Rates of mucositis, nausea/vomiting, diarrhea, bleeding and infections were similar in the two groups. Median overall survival and event-free survival did not differ significantly between the two groups. These findings indicate that BuCyE is an effective conditioning regimen, showing similar survival outcomes and toxicity profiles as BEAM. Furthermore, hematologic recovery is significantly faster in patients given the BuCyE conditioning regimen.