Hong Jae Chon

Treatment Outcomes of Sunitinib Treatment in Advanced Renal Cell Carcinoma Patients: A Single Cancer Center Experience in Korea

PURPOSE The retrospective study was performed to assess the efficacy and toxicity profiles of sunitinib in Korean patients with metastatic renal cell carcinoma (RCC). MATERIALS AND METHODS Between January 2005 and December 2008, 76 Korean patients with recurrent/metastatic RCC who received sunitinib were retrospectively reviewed. The primary end point was progression-free survival and the secondary end points were overall survival and response rate. We also assessed the toxicities associated with sunitinib treatment. RESULTS Of the 76 patients, 69 (90.1%) were diagnosed with clear cell RCC. The median progression-free survival and overall survival were 7.2 and 22.8 months, respectively in overall patients. Sixty-two patients (81.6%) received 50 mg 4 week and 2 week off schedule, and 14 patients (18.4%) received 37.5 mg daily on a daily continuous schedule. The objective response rate and disease control rate were 27.6% and 84.2%, respectively. A dose reduction or reduction in dose due to adverse events occurred in 76% of the patients, whereas 11% of the patients had discontinued treatment. Other common laboratory abnormalities were increased serum creatinine (75.6%), elevated alanine aminotransferase (71.0%), neutropenia (61.8%), anemia (69.7%), and increased aspartate aminotrasferase (53.3%). Grade 3/4 toxicities occurred as follows: thrombocytopenia (38.2%), fatigue (10.5%), stomatitis (10.5%), and hand-foot syndrome (9.2%). CONCLUSION Our results indicate that sunitinib treatment is effective and tolerable for ecurrent/metastatic RCC patients in Korea. Further studies with prognostic or biochemical factors are needed to clarify the different toxicity profiles of this study.

Clinical Value of Ezrin Expression in Primary Osteosarcoma

PURPOSE Ezrin is a membrane cytoskeletal linker protein and it is known to be associated with metastasis of primary osteosarcoma. The aim of this study is to determine the relationship between an ezrin expression and several key clinical parameters and to elucidate its potential prognostic value for patients with osteosarcoma. MATERIALS AND METHODS Seventy patients with histologically confirmed osteosarcoma and who had no distant metastasis were enrolled between 1995 and 2005 at Yonsei Cancer Center, Severance Hospital, Korea. The clinical parameters were retrospectively reviewed and immunohistochemical staining (IHC) for ezrin was performed using the surgically resected specimens. RESULTS Of the 70 tumor specimens, 39 (55.7%) revealed an ezrin expression. More of an osteoblastic histology and an elevated initial ALP level were observed in the ezrin positive patients than in the ezrin negative patients (p=0.008 and 0.001, respectively). The proportion of patients who favorably responded to neoadjuvant chemotherapy (≥or=90% necrosis) was significantly higher in the group of ezrin positive patients than that in the group of ezrin negative patient (72.2% vs 45.2%, respectively, p=0.024). The ezrin positive patients showed more frequent recurrence than did the ezrin negative patients (64.1% vs 35.5%, respectively, p=0.017). The patients with an ezrin expression also demonstrated poorer survival than did those patients without ezrin expression (5-year EFS: 31.7% vs 61.3%, respectively, p=0.023, 5-year OS: 53.4% vs 71.0%, respectively, p=0.022). When comparing EFS according to both an ezrin expression and chemoresponsiveness, there were trends that the ezrin negative/chemoresponsive group showed the best 5-year EFS (71.4%), followed by the ezrin negative/chemoresistant group (52.9%), the ezrin positive/chemoresponsive group (38.1%) and the ezrin positive/chemoresistant group (13.6%). These trends were statistically significant (p=0.036). CONCLUSION The expression of ezrin by IHC staining was found in 55.7% of the patients with metastasis-free osteosarcoma. Immunoreactivity to ezrin is a negative prognostic factor for survival for the patients suffering with osteosarcoma. Identifying an ezrin expression might offer a valuable piece of information when treating patients with primary osteosarcoma.

Docetaxel versus paclitaxel combined with 5-FU and leucovorin in advanced gastric cancer: combined analysis of two phase II trials.

PURPOSE This is an ad hoc analysis of two phase II studies which compared the efficacy and safety of two taxanes (paclitaxel and docetaxel) combined with 5-fluorouracil (5-FU) and leucovorin (LV) in advanced gastric cancer. MATERIALS AND METHODS Patients with advanced gastric adenocarcinoma who were untreated or had only received first-line chemotherapy, were treated with either paclitaxel (PFL; 175 mg/m(2)) or docetaxel (DFL; 75 mg/m(2)) on day 1, followed by a bolus of LV (20 mg/m(2) days 1~3) and a 24-hour infusion of 5-FU (1,000 mg/m(2) days 1~3) every 3 weeks. The primary endpoint was overall response rate (ORR) and the secondary endpoint included survival and toxicity. RESULTS Sixty-six patients received DFL (first-line [n=38]; and second-line [n=28]) and 60 patients received PFL (first-line [n=37]; and second-line [n=23]). The ORRs were not significantly different between the 2 groups (DFL, 26%; PFL, 38%). With a median follow-up of 9.5 months, the progression free survival was 5.2 months (95% confidence interval [CI], 4.2~6.5 months) for DFL and 3.3 months (95% CI, 1.3~5.5 months) for PFL (p=0.17). The overall survival was also comparable between the patients who received DFL and PFL (10.0 months [95% CI, 7.2~12.5 months] and 13.9 months [95% CI, 10.9~19.2 months], respectively; p=0.37). The most frequent grade 3~4 adverse event was neutropenia (DFL, 71%; PFL, 62%). DFL and PFL had different non-hematologic toxicities; specifically, grade >or=3 mucositis (5%) and diarrhea (3%) were common in DFL, while nausea/vomiting (15%) and peripheral neuropathy (5%) were common in PFL. CONCLUSION Thus, the two taxanes had similar efficacy in the treatment of advanced gastric cancer, but different toxicity profiles. Prospective comparative studies are required to further clarify the role of taxanes in the treatment of advanced gastric cancer.

Differential Prognostic Implications of Gastric Signet Ring Cell Carcinoma: Stage Adjusted Analysis from a Single High-volume Center in Asia

Objective: The aim of this study was to analyze the clinicopathologic characteristics and prognosis of signet ring cell carcinoma (SRC) according to disease status (early vs advanced gastric cancer) in gastric cancer patients. Background: The prognostic implication of gastric SRC remains a subject of debate. Methods: A retrospective analysis was performed using the clinical records of 7667 patients including 1646 SRC patients who underwent radical gastrectomy between 2001 and 2010. A further analysis was also performed after dividing patients into three groups according to histologic subtype: SRC, well-to-moderately differentiated (WMD), and poorly differentiated adenocarcinoma. Results: SRC patients have younger age distribution and female predominance compared with other histologic subtypes. Notably, the distribution of T stage of SRC patients was distinct, located in extremes (T1: 66.2% and T4: 20%). Moreover, the prognosis of SRC in early gastric cancer and advanced gastric cancer was contrasting. In early gastric cancer, SRC demonstrated more favorable prognosis than WMD after adjusting for age, sex, and stage. In contrast, SRC in advanced gastric cancer displayed worse prognosis than WMD. As stage increased, survival outcomes of SRC continued to worsen compared with WMD. Conclusions: Although conferring favorable prognosis in early stage, SRC has worse prognostic impact as disease progresses. The longstanding controversy of SRC on prognosis may result from disease status at presentation, which leads to differing prognosis compared with tubular adenocarinoma.

Prognosis of pN3 Stage Gastric Cancer

PURPOSE The aim of this study was to determine the prognosis of pN3 stage gastric cancer patients after they have undergone curative resection, and we also wanted to identify the prognostic factors according to the clinico-pathologic features. MATERIALS AND METHODS Between January 2000 and December 2004, we retrospectively reviewed the medical records of the patients with histologically confirmed pN3 stage gastric cancer. They underwent both gastrectomy and lymphadenectomy with a curative aim. We categorized the pN3 stage patients into 2 groups; one with pN3 only (pN3M0) and the other with pN3 combined with M1 stage (pN3M1) that included peritoneal seeding, hepatic metastasis or para-aortic LN metastasis. RESULTS Out of 467 patients with stage IV gastric adenocarcinoma who received surgery, 260 patients underwent curative resection and they were pathologically staged as N3. Among these 260 patients, 78 patients were classified as the pN3/M1 stage. For all the patients, the median follow-up period was 19 months (range: 1~108 months) and the median overall survival time was 16.2 months (95% CI, 14.1~18.3%). The 5-year survival rate of the pN3/M0 group was significantly higher than that of the pN3/M1 group (12.6% vs. 2.6%, respectively, p<0.0001). The identified predictor for a worse prognosis was an advanced T4 stage (HR: 3.38, 95% CI, 1.4~8.3, p=0.008) for the pN3 patients. CONCLUSION The survival for the pN3 gastric cancer patients after curative gastrectomy was significantly longer in the pN3/M0 group as compared to that of the pN3/M1 group. An advanced T stage was a predictor for a poor prognosis for the pN3 patients. Therefore, diverse treatment strategies for these heterogeneous pN3 gastric cancer patients are needed for improving their survival.

PTEN loss and level of HER2 amplification is associated with trastuzumab resistance and prognosis in HER2-positive gastric cancer

Background Trastuzumab is an active agent against human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC). This study aimed to characterize resistance to trastuzumab-based front-line chemotherapy in HER2+ GC patients and to establish factors predictive of this resistance. Results Among 129 HER2+ GC patients, 25% displayed rapid disease progression within 4 months from initiation of therapy. These patients showed a higher rate of signet ring cell histology, bone metastasis, poor performance status, frequent loss of PTEN expression, and low HER2 amplification index compared with patients who were progression-free for at least 4 months. In contrast, there was no significant difference in the frequency of the PIK3R1 variant. Multivariate analyses confirmed two independent molecular predictors for trastuzumab resistance: loss of PTEN expression and low HER2 amplification index (<5). Patients with one or both molecular predictors at diagnosis exhibited worse progression-free and overall survival compared to those without risk factors (p < 0.001 and p = 0.001, respectively). Conclusion In HER2+ GC patients, loss of PTEN expression and low HER2 AI correlated with resistance to trastuzumab-based therapy and dismal prognosis. Since patients harboring these molecular predictors are unlikely to respond to trastuzumab-based therapy, other novel therapeutic targets needed to be considered. Methods HER2+ GC patients who were treated with trastuzumab in combination with either 5-fluorouracil/cisplatin or capecitabine/cisplatin were enrolled. Clinicopathologic features and molecular alterations of HER2, phosphoinositide 3-kinase regulatory subunit 1 (PIK3R1), and phosphatase and tensin homolog (PTEN) were correlated with treatment outcome. Factors predictive of resistance were also explored.

Predictive Nomogram for Recurrence of Stage I Colorectal Cancer After Curative Resection

Micro‐Abstract: In a study that aimed to develop a predictive nomogram for postoperative recurrence in stage I colorectal cancer (CRC), a predictive nomogram was developed with a total of 1538 stage I CRC patients and internally validated. This nomogram will assist physicians to more accurately identify high‐risk patients who need more active surveillance and will help ensure more efficient disease management. Background: Patients with stage I colorectal cancer (CRC) have excellent prognosis after curative surgery. However, approximately 5% to 10% of patients experience recurrence and have a poor prognosis. Because the incidence of stage I CRC is increasing with active screening programs worldwide, a more accurate and easy‐to‐use predictive tool for recurrence is becoming more important. This study aimed to develop a predictive nomogram for recurrence in stage I CRC. Patients and Methods: A total of 1538 patients who underwent curative surgery for stage I CRC were enrolled. Predictive factors for recurrence were determined by multivariate Cox regression model and were used to develop a predictive nomogram. This model was internally validated, and performance was evaluated through calibration plots. Results: The cumulative recurrence rate at 5 years after surgery for stage I CRC was 5.3%. In multivariate Cox analysis, independent predictors of recurrence were tumor location at rectum, pT2 stage, and presence of lymphovascular invasion. The 5‐year recurrence rate was significantly different depending on the number of risk factors (0.7% for 0, 5.8% for 1, and 9.7% for ≥ 2 risk factors). On this basis, a nomogram for recurrence‐free survival was developed and internally validated. The concordance index of the nomogram was 0.71, and the performance was acceptable. Conclusion: We developed and internally validated a nomogram that can predict postoperative recurrence in stage I CRC patients. This nomogram may be used to more accurately stratify the risk of recurrence and to perform personalized postoperative surveillance in stage I CRC patients.

Different subtypes of epithelioid sarcoma and their clinical implication: long-term multi-institutional experience with a rare sarcoma

Epithelioid sarcoma (ES) is a very rare soft‐tissue sarcoma with a high tendency of recurrence and metastasis. We analyzed clinical features of ES and aimed to identify the potential role of radio‐ and chemotherapy in ES. Fifty‐five patients diagnosed with ES between 1997 and 2014 were enrolled from seven tertiary hospitals in Korean Cancer Research Group. The clinical variables were retrospectively reviewed and analyzed. Forty‐six (84%) patients underwent surgical resection of ES, and among them, 27 experienced recurrence. In these patients, resection margin status and adjuvant radiotherapy were independent prognostic factors for longer recurrence‐free survival (RFS), while adjuvant chemotherapy did not influence RFS. Twenty‐two (40%) patients received palliative chemotherapy for metastatic or recurrent ES, and in these patients, palliative chemotherapy was the only independent prognostic factor for longer overall survival. Intriguingly, the clinical benefit of radio‐ and chemotherapy was observable only in proximal ES, but not in extremity ES, indicating that subtypes of ES might respond to radio‐ or chemotherapy differently. Proximal ES seems to benefits more from active anticancer treatment than conventional extremity ES. The aggressive characteristics of proximal ES could be overcome with an optimal multimodal treatment.

Rho GTPase RhoJ is Associated with Gastric Cancer Progression and Metastasis

Rho GTPases play a pivotal role in tumor progression by regulating tumor cell migration and invasion. However, the role of Rho GTPases in gastric cancer (GC) remains unexplored. This study aimed to investigate the clinical implications of RhoJ, which is an uncharted member of Rho family. RhoJ expression in human GC cell lines and surgical specimens from GC patients were analyzed. Moreover, in vitro gain-of-function analysis was performed to evaluate the malignant phenotypes of RhoJ-overexpressing GC cells. The extent of RhoJ expression varied among GC cell lines and GC patients. YCC-9 cell line displayed the strongest expression, while YCC-10, -11, and -16 showed scant expressions. Of the 70 GC patients, 34 (48.6%) had RhoJ expression in their GC tissue, and patients with high RhoJ expression had more diffuse type GC (73.5% vs. 41.7%), were at more advanced stages (stage III, IV: 85.3% vs. 58.4%), and had more frequent metastasis (47.1% vs. 11.1%), denoting that RhoJ has a potential role in GC progression and metastasis. High RhoJ expression significantly correlated with poor overall survival and recurrence-free survival after surgical resection of gastric cancer. Finally, In vitro gain-of-function experiments showed 41.3% enhanced motility and 60.4% enhanced invasiveness in RhoJ-overexpressing GC cells compared to control, with negligible difference in cell proliferation. Collectively, high RhoJ expression is an independent negative prognostic factor for the survival outcome of GC and correlated with the increased cell motility and invasiveness.

The clinical implications of FDG-PET/CT differ according to histology in advanced gastric cancer

BackgroundThe prognostic impact of preoperative 18F-FDG PET/CT in advanced gastric cancer (AGC) remains a matter of debate. This study aims to evaluate the prognostic impact of SUVmax in preoperative 18F-FDG PET/CT of AGC according to histologic subtype, with a focus on the differences between tubular adenocarcinoma and signet ring cell (SRC) carcinoma.MethodsAs a discovery set, a total of 727 AGC patients from prospective database were analyzed according to histologic subtype with Cox proportional hazard model and p-spline curves. In addition, another 173 patients from an independent institution was assessed as an external validation set.ResultsIn multivariate analysis, high SUVmax in preoperative 18F-FDG PET/CT of AGC was negatively correlated with disease-free survival (DFS) and overall survival (OS) in patients with diffuse type (DFS: HR 2.17, P < 0.001; OS: HR 2.47, P < 0.001) or SRC histology (DFS: HR 2.26, P = 0.005; OS: HR 2.61, P = 0.003). This negative prognostic impact was not observed in patients with intestinal type or well or moderately differentiated histology. These findings have been consistently confirmed in a validation set. The p-spline curves also showed a gradual increase in log HR as SUVmax rises only for SRC histology and for diffuse-type AGC. Finally, a novel predictive model for recurrence of AGC with diffuse type or SRC histology was generated and validated based on the preoperative SUVmax.ConclusionsPreoperative high SUVmax of AGC is a poor prognostic factor in those with diffuse type or SRC histology. This study is the first to demonstrate the differential prognostic impact of preoperative PET/CT SUVmax in AGC according to histologic subtype and provide a clue to explain previous discrepancies in the prognostic impact of preoperative PET/CT in AGC. Prospective studies are required to validate the role of preoperative SUVmax in AGC.