Kwonoh Park

Comparative Efficacy of Sunitinib versus Sorafenib as First-Line Treatment for Patients with Metastatic Renal Cell Carcinoma

Background: This study investigated the efficacy and toxicity of sorafenib and sunitinib as primary treatment for patients with metastatic renal cell carcinoma (mRCC). Methods: We identified 49 and 220 patients treated with sorafenib and sunitinib, respectively, as first-line therapy in the Asan Medical Centre from April 2005 to March 2011. Results: Disease control rates of 71 and 74% were achieved with sorafenib and sunitinib, respectively (p = 0.687). After a median follow-up of 27.6 months, progression-free survival (PFS) and overall survival (OS) were not significantly different between the sorafenib and the sunitinib group (PFS 8.6 vs. 9.9 months, respectively, p = 0.948, and OS 25.7 vs. 22.6 months, p = 0.774). Patients treated with sorafenib required dose reduction due to toxicities less frequently than those treated with sunitinib (37 vs. 54%, p = 0.034). Haematological toxicity of grade 3 or 4 was more common in the sunitinib group than in the sorafenib group (45 vs. 4%, p < 0.001). Multivariate analysis showed old age, Hengs risk group, and bone and liver metastases, but not the type of vascular endothelial growth factor tyrosine kinase inhibitor, were independent prognostic factors affecting OS. Conclusion: The results of this study indicate that sorafenib has comparable efficacy to sunitinib in the treatment of mRCC patients and fewer and less severe toxicities, but the number of patients included in the study was small.

p16 immunohistochemistry alone is a better prognosticator in tonsil cancer than human papillomavirus in situ hybridization with or without p16 immunohistochemistry.

Abstract Conclusions: p16 immunohistochemistry (IHC) status correlated with less exposure to smoking and/or alcohol in Korean patients with locally advanced tonsillar squamous cell carcinoma (TSCC), and was an independent prognostic factor for survival. Objective: TSCC is more likely to be human papillomavirus (HPV)-positive than other head and neck squamous cell carcinoma (HNSCC) subtypes. The objective of this study was to ascertain the HPV status of TSCC in Korean patients and to determine its relationship with clinical parameters and prognosis. Methods: The locally advanced TSCCs of 79 patients who were treated between 2000 and 2008 were tested by p16 IHC and HPV in situ hybridization (ISH) with a tissue microarray. Results: Sixty-three patients (80%) were positive for p16 IHC, while 54 (68%) were positive by HPV ISH. p16 IHC status correlated significantly with lower exposure to smoking and alcohol (p < 0.05) but did not correlate with T and N stage classification, histological differentiation, age, or gender. The p16-positive group had a significantly higher 5-year overall survival rate in comparison with the p16-negative group (78% vs 63%, hazard ratio (HR) = 0.347, 95% CI = 0.14, 95% Cp = 0.025). p16 IHC was a favorable independent prognostic factor for overall survival, even after adjustment for age and T stage (HR = 0.283, 95% CI = 0.103, 95% p = 0.015).

Efficacy and Safety of Everolimus in Korean Patients with Metastatic Renal Cell Carcinoma Following Treatment Failure with a Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor

Purpose The purpose of this study is to assess the efficacy and safety of everolimus in Korean patients with metastatic renal cell carcinoma (mRCC) for whom initial treatment with a vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) has failed. Materials and Methods Eligible patients with mRCC (any histology) who had progressed on or were intolerant of VEGFr-TKI therapy received oral everolimus (10 mg dose once daily). Tumor response was reassessed according to Response Evaluation Criteria in Solid Tumors (RECIST). Results This study included 100 patientswith a median follow-up duration of 10.2 months, a median progression-free survival (PFS) of 4.2 months (95% confidence interval [CI], 3.4 to 5.0 months), and an overall survival of 10.1 months (95% CI, 6.9 to 13.3 months). The most common grade 3 or greater adverse events (AEs) overall were anemia (13%), pneumonitis (9%), hyperglycemia (8%), and stomatitis (6%). While the incidence of pneumonitis was similar (26 cases, 26%) to the reported incidence in Western patients, the Korean presentations were more severe: 10 patients permanently discontinued everolimus due to pneumonitis, including two deaths on treatment. Statistically significant relationships were established between biologic toxicities, hyperglycemia and anemia, and PFS (hyperglycemia vs. non-hyperglycemia: hazard ratio [HR], 0.61; p=0.055 and anemia vs. non-anemia: HR, 0.51; p=0.021). Conclusion Everolimus was effective in Korean patients with mRCC who had failed initial VEGFr-TKI therapy. While everolimus was well tolerated in general and the AE incidence of this study was similar to those of previous reports, severe pneumonitis was common. Hyperglycemia and anemia showed significant correlation with PFS and thus may be potentially useful as prognostic indicators.

Response evaluation criteria in solid tumors response of the primary lesion in metastatic renal cell carcinomas treated with sunitinib: does the primary lesion have to be regarded as a target lesion?

BACKGROUND We evaluated whether best overall response changes by designating primary renal lesions as either target or nontarget lesions and assessing response per Response Evaluation Criteria in Solid Tumors in mRCC patients treated with sunitinib. In addition, we evaluated whether discordance, if any, leads to a difference in predictive value of response in terms of time to progression (TTP) and overall survival (OS). PATIENTS AND METHODS Patients with mRCC with an intact primary tumor and at least 1 extrarenal measurable lesion were included in this study. The variation of the sum of diameters (ΔSOD) of target lesions and best overall response, assessed from all target lesions and from metastasis-only target lesions, was documented separately. RESULTS There were 41 patients included. Median ΔSOD of the primary lesion and metastatic target lesion were -6.0% (range, -34.0% to 17.6%), and -18.0% (range, -100.0% to 120.0%), respectively. For metastasis-only target lesions, the best overall response of 2 patients (4.9%) changed from stable disease to partial response. When we categorized patients into responders and nonresponders, response determination using metastasis-only target lesions resulted in significantly better discrimination of time to progression (14.9 vs. 4.3 months, P = .001) and overall survival (18.5 vs. 9.6 months, P = .036) between 2 groups. Using all target lesions, both TTP (14.9 vs. 5.4 months, P = .056) and OS (18.0 vs. 10.6 months, P = .155) were not statistically significant. CONCLUSION When treating nonnephrectomized mRCC patients, selecting metastasis-only lesions as target lesions might be better to determine response, which might be more representative of survival end point.

Efficacy of assessing circulating cell-free DNA using a simple fluorescence assay in patients with triple-negative breast cancer receiving neoadjuvant chemotherapy: a prospective observational study

This study aims to assess cell-free DNA (CFD) by a fluorescence assay as a biomarker for early prediction of a pathologic complete response (pCR) and relapse in patients with triple-negative breast cancer (TNBC) undergoing neoadjuvant chemotherapy. Patients with clinical stage II or III TNBC scheduled for neoadjuvant chemotherapy were prospectively enrolled. All patients underwent four cycles of Adriamycin plus cyclophosphamide (AC), followed by four cycles of cisplatin or docetaxel chemotherapy and surgery. Blood samples were obtained before the initial chemotherapy (baseline-CFD) and after four AC neoadjuvant chemotherapy cycles (AC-CFD) to evaluate CFD levels. In total, 72 patients who met the inclusion criteria were enrolled. The mean baseline-CFD and AC-CFD levels were 239 ± 68 and 210 ± 66 ng/mL, respectively, with a significant decline in the CFD levels after AC neoadjuvant chemotherapy (P = 0.001). In the 33.6-month median follow-up, 18 cases of relapse were reported. A ROC curve analysis of baseline-CFD was performed to determine the predictive value for relapse, and an area under the curve of 0.62 (95% CI, 0.46–0.78) at 264 ng/mL was obtained. Patients with baseline-CFD >264 ng/mL were at a higher risk of relapse than those with baseline-CFD ≤264 ng/mL (HR, 2.84; 95% CI, 1.11–7.24; P = 0.029). Multivariate analysis established baseline-CFD as an independent predicting factor for relapse (HR, 3.74; 95% CI, 1.32–10.53; P = 0.013). In conclusion, baseline-CFD measured by a fluorescence assay might be a potential biomarker to predict relapse, which could be useful for risk stratification of TNBC.

Incidence of venous thromboembolism and the role of D-dimer as predictive marker in patients with advanced gastric cancer receiving chemotherapy: A prospective study

AIM To investigated the incidence and risk factors of venous thromboembolism (VTE) in patients with advanced gastric cancer (AGC) receiving chemotherapy. METHODS All consecutive chemotherapy-naïve patients with AGC who would receive palliative chemotherapy between November 2009 and April 2012 in our hospital were recruited. Their pretreatment clinical and laboratory variables, including D-dimer, were recorded. The frequency of VTE development and survival rates during each chemotherapy cycle and regularly thereafter were assessed. RESULTS A total of 241 patients enrolled between November 2009 and April 2012 were analyzed. During a median follow-up duration of 10.8 mo (95%CI: 9.9-11.7), 27 patients developed VTE and the incidence of VTE was 17.5% (95%CI: 10.5-24.0, 12.0 events/100 person-years). The 6-mo and 1-year cumulative incidences were 7.8% (95%CI: 4.2%-11.4%) and 12.4% (95%CI: 7.3-17.2), respectively. Thirteen (48.1%) patients were symptomatic and the other 14 (51.9%) patients were asymptomatic. In multivariate analysis, pretreatment D-dimer level was the only marginally significant risk factor associated with VTE development (hazard ratio = 1.32; 95%CI: 1.00-1.75, P = 0.051). CONCLUSION The incidence of VTE is relatively high in patients with AGC receiving chemotherapy, and pretreatment D-dimer level might be a biomarker for risk stratification of VTE.

Changes of pulmonary function test and development of non-infectious pneumonitis in patients with metastatic renal cell carcinoma treated with everolimus.

530 Background: The aim of this study was to evaluate the changes of pulmonary function test (PFT) during everolimus treatment and to assess whether the change of PFT is associated with the development of non-infectious pneumonitis in patients with metastatic renal cell carcinoma. In addition, we tried to determine whether everolimus-associated pneumonitis could affect the efficacy of everolimus. Methods: Patients with mRCC who had received everolimus (10 mg dose once daily) after failure to VEGF-TKI treatment and underwent baseline PFT with regular PFT follow up were included in this study. The diffusing capacity divided by the alveolar volume (DLCO/VA) was used among various parameters of PFT. Repeated-measures ANOVA was used to describe changes of DLCO/VA. A Cox proportional hazard model with pneumonitis onset as a time-dependent covariate used to assess the prognostic role of pneumonitis. Results: This study included 36 patients. Nine patients (30%) developed everolimus-associated pneumonitis (pneumon...

Korean population-based external validation of western prognostic models for survival in metastatic renal cell cancer.

464 Background: Prognostic models have been proposed to predict factors affecting survival in metastatic renal cell cancer (RCC). We retrospectively reviewed clinical features and survival data to validate MSKCC and Hengs models in Korean metastatic RCC patients. METHODS 270 patients with first-line Vascular Endothelial Growth Factor (VEGF) targeted therapy, regardless of prior immunotherapy, were enrolled. We reviewed medical records to find clinical factors affecting overall survival (OS). Predictive accuracy for survival of two models was evaluated by Harrells concordance-index (c-index). RESULTS From 2005 to 2010, 197 males (72.6%) and 73 females received therapy at a median age of 58 years (range, 17 - 86). After median follow-up of 16.0 months (range 0.0 - 78.0), median OS (mOS) was 22.7 months (95% CI, 18.3 - 27.1). 55 patients (20.4%) had prior immune therapies and 162 (60.4%) were initially metastatic. None was treated with bevacizumab, thus 221 (81.9%) were treated with sunitinib and 49 with sorafenib. Multivariate analysis showed 5 of Hengs factors were independent: Karnofsky scale < 80% (HR = 1.53, 95% CI 1.01 - 2.31, p=0.047), from diagnosis to treatment < 1 year (HR=1.94, 95% CI 1.35 - 2.79, p < 0.001), anemia (HR 1.66, 95% CI 1.13 - 2.43, p = 0.010), hypercalcemia (HR = 1.92, 95% CI 1.21 - 3.05, p=0.006) and neutrophilia (HR = 1.96, 95% CI 1.21 - 3.16, p = 0.006). Validation of MSKCC and Hengs model showed c-index of 0.836 (95% CI, 0.698 - 0.941) and 0.800 (95% CI, 0.655 - 0.915), each. We further applied each models stratification by risk grouping. First with MSKCC (log-rank p < 0.001), mOS in no risk (n = 80), 1 risk (n = 128) and 2 or more risks (n=51) were 35.5 months (95% CI, 24.0 - 47.0), 23.7 months (95% CI, 18.2 - 29.2) and 7.4 months (95% CI, 4.5 - 10.3), respectively. Second with Hengs (log-rank p < 0.001), mOS in favorable (no adverse factors, n = 37), intermediate (one or two adverse factors, n = 161) and poor (three to six adverse factors, n=61) were respectively 43.8 months (95% CI, 31.8 - 55.8), 25.4 months (95% CI, 21.5 - 29.3) and 7.5 months (95% CI, 4.9 - 10.1). CONCLUSIONS Western prognostic models were accurate and feasible in Korean metastatic RCC patients treated with anti-VEGF therapy.

Does primary lesion have to be regarded as a target lesion when evaluating response in metastatic renal cell carcinoma (mRCC) treated with sunitinib

425 Background: Primary lesion in mRCC often shows necrotic change or only density changes to targeted therapy. As most clinical trials for mRCC have enrolled nephrectomized patients (pts), there is no consensus on including primary lesion in target lesion when evaluating response. We investigated whether best overall response (OR) changes when designate target lesions with or without primary lesion, and such discordance lead to difference in predictive value in terms of time to progression (TTP) and overall survival (OS). METHODS We enrolled mRCC pts with intact primary lesion, at least one measurable metastatic lesion, and proper image data who had received sunitinib in our institution between 2003 and 2011. We documented the variation of the sum of the largest diameters (ΔSLD) with all target lesions and with metastasis-only target lesions separately. Response evaluation was calculated with RECIST v1.1. RESULTS Of 41 pts, 38 received sunitinib as 1st line treatment and 3 did as 2nd line. The most frequent metastatic site was lung (63.4%) followed by lymph node (46.3%) and bone (42.5%). Median ΔSLD of primary lesion and metastatic target lesion were -6.02% (range: -34.00 to 17.60%), and -18.03% (-100.00 to 120.00%). On response evaluation with metastasis-only target lesions, best OR of 2 pts (4.87%) changed from stable disease to partial response. When categorize pts into responders and non-responders, metastasis-only target lesions resulted in significantly better discrimination of TTP (14.949 vs 4.271 mo, p=0.01) and OS (18.497 vs 9.561 mo, p=0.036) between two groups. Using all target lesions, both TTP (14.949 vs 5.355 mo, p=0.056) and OS (17.971 vs 10.579 mo, p=0.155) were statistically insignificant. CONCLUSIONS Our study showed discordance in OR between using all target lesions and using metastasis-only target lesions, and metastasis-only target lesion could have more accurate predictive value. As response rate is often used as an end point in clinical research of mRCC, further discussion is needed whether primary lesion should be included or not in target lesion. [Table: see text].

Incidence and Risk Factors for the Development of Prolonged Severe Intrahepatic Cholestasis After Pediatric Living-Donor Liver Transplantation

The aim of this study is to evaluate the incidence, etiology, and risk facrors for prolonged severe intrahepatic cholestasis (PSIC) after 129 pediatric living-donor liver transplantations (LDLT). The incidence of PSIC was 25.6% (n = 33). Twenty-eight (84.8%) versus 5 (15.2%) children experienced early versus late PSIC, respectively. Among these 33 children with PSIC, 8 (24.2%) received a donor liver with mild to moderate fatty change, 4 (12.1%) with low graft-body weight ratios, and 4 (12.1%) with ABO incompatibility. The predominant etiologies were acute rejection (n = 15; 45.5%), chronic rejection (n = 6; 18.2%), virus (n = 3; 9.1%), vascular complications (n = 4; 12.1%), and initial graft dysfunction (n = 10; 30.3%). ABO incompatibility (P = .032; odds ratio [OR] 3.25), chronic rejection (P = .012; OR 4.76), and vascular complications (P = .046; OR 1.82) were significant variables associated with PSIC. Donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications may be important to prevet PSIC in LDLT.