Seok Yun Kang

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.

Phase III, Multicenter, Randomized Trial of Maintenance Chemotherapy Versus Observation in Patients With Metastatic Breast Cancer After Achieving Disease Control With Six Cycles of Gemcitabine Plus Paclitaxel As First-Line Chemotherapy: KCSG-BR07-02

PURPOSE The primary purpose of our study was to evaluate whether maintenance chemotherapy with paclitaxel/gemcitabine (PG) was superior to observation in improving progression-free survival (PFS) in patients with metastatic breast cancer (MBC) who achieved disease control with an initial six cycles of PG as their first-line treatment. PATIENTS AND METHODS The study was a prospective, randomized, multicenter, phase III trial. Patients MBC with who achieved disease control after six cycles of PG chemotherapy were randomly assigned to maintenance chemotherapy or observation until progression. RESULTS Of 324 patients from 10 centers enrolled, 231 patients with MBC exhibited disease control (complete response + partial response + stable disease) with first-line PG and were randomly assigned to maintenance chemotherapy (n = 116) or observation (n = 115). The median age was 48 years (range, 28 to 76 years), median follow-up was 33 months, and median number of chemotherapy cycles in the maintenance group after random assignment was six. The median PFS time after random assignment was longer in the maintenance group than in the observation group (7.5 v 3.8 months, respectively; P = .026). The median overall survival (OS) time was longer in the maintenance group than in the observation group (32.3 v 23.5 months, respectively; P = .047). The rate of grade 3 or higher neutropenia after random assignment was higher in the maintenance group than in the observation group (61% v 0.9%, respectively; P < .001). CONCLUSION In patients with MBC who achieved disease control with an initial six cycles of PG chemotherapy, maintenance PG chemotherapy resulted in better PFS and OS compared with observation.

Expression of excision repair cross-complementation group 1 protein predicts poor outcome in advanced non-small cell lung cancer patients treated with platinum-based doublet chemotherapy

BACKGROUND Alterations in apoptosis and DNA damage repair related proteins are associated with resistance to chemotherapy, which is the most important cause of treatment failure in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Pretreatment tumor biopsy specimens from 50 patients with NSCLC including stage IIIB with malignant pleural effusion or stage IV or recurrent disease were analyzed for p53, Bcl-2, Bax, and ERCC1 expression by immunohistochemistry. All patients were treated with platinum-based third-generation doublet chemotherapy, in which gemcitabine and cisplatin was the most commonly administered regimen (17 patients). RESULTS High expression of p53, Bcl-2, Bax, and ERCC1 was observed in 24 (48%), 8 (16%), 32 (63%), and 28 (55%) patients, respectively. In univariate analysis, high expression of ERCC1 demonstrated a trend of association with poor overall survival (OS) (median, 8 months vs. 11 months; P=0.055). High expression of p53, Bcl-2, Bax was not correlated with patient outcome. High expression of ERCC1 was an independent prognostic factor for poor OS (P=0.002) along with poor performance status (P=0.028) and lack of disease control (P=0.001) in multivariate analysis. CONCLUSIONS High expression of ERCC1 may be a useful prognostic factor for poor outcome in advanced NSCLC patients treated with platinum and third-generation doublet chemotherapy.

Differential diagnosis in idiopathic granulomatous mastitis and tuberculous mastitis.

Purpose Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory disease of unknown etiology. The diagnosis of IGM requires that other granulomatous lesions in the breast be excluded. Tuberculous mastitis (TM) is also an uncommon disease that is often difficult to differentiate from IGM. The purpose of this study is to develop a new algorithm for the differential diagnosis and treatment of IGM and TM. Methods Medical records of 68 patients (58 with IGM and 10 with TM) between July 1999 and February 2009 were retrospectively reviewed. Results The mean age of the patients was 33.5 (IGM) and 40 (TM) years (p=0.018). The median follow-up was 84 months. Of the total 10 patients with TM, 5 patients had a history of pulmonary tuberculosis. The most common symptoms of the diseases were breast lump and pain. However, axillary lymphadenopathy was more seen in TM (50%) compared to IGM (20.6%) (p=0.048). TM showed more cancer-mimicking findings on radiologic study (p=0.028). In IGM, 48 patients (82.7%) underwent surgical wide excision and 21 patients (36.2%) were managed with corticosteroid therapy and antibiotics. All of the TM patients received anti-tuberculosis medications and 9 patients (90%) underwent wide excision. The mean treatment duration was 2.8 months in IGM and 8.4 months in TM. Recurrence developed in 5 patients (8.6%) in IGM and 1 patient (10%) in TM. Conclusion This study shows different characteristics between IGM and TM. The IGM patients were younger and had more mastalgia symptoms than the TM patients. Axillary lymphadenopathy was seen more often in TM patients. Half of the TM patients had pulmonary tuberculosis or tuberculosis lymphadenitis. Surgical wide excision might be both therapeutic and useful for providing an exact diagnosis.

A novel algorithm for detection of adverse drug reaction signals using a hospital electronic medical record database

Quantitative analytic methods are being increasingly used in postmarketing surveillance. However, currently existing methods are limited to spontaneous reporting data and are inapplicable to hospital electronic medical record (EMR) data. The principal objectives of this study were to propose a novel algorithm for detecting the signals of adverse drug reactions using EMR data focused on laboratory abnormalities after treatment with medication, and to evaluate the potential use of this method as a signal detection tool.

Low expression of Bax predicts poor prognosis in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy.

Purpose: The present study evaluated the prognostic significance of apoptosis-related proteins, p53, Bcl-2, Bax, and galectin-3 in patients with locally advanced esophageal cancer treated with definitive chemoradiotherapy. Experimental Design: A total of 63 patients with locally advanced esophageal cancer (squamous cell carcinoma: 62; adenocarcinoma: 1; stages II-IV) were treated with definitive chemoradiotherapy using 5-fluorouracil and cisplatin combined with radiotherapy. Pretreatment tumor biopsy specimens were analyzed for p53, Bcl-2, Bax, and galectin-3 expression by immunohistochemistry. Results: High expression of Bax, p53, Bcl-2, and galectin-3 was observed in 67%, 47%, 24%, and 29% of patients, respectively. The median overall survival (OS) of total patients was 14 months with 16% of 3-year OS. High expression of p53, Bcl-2, and galectin-3 did not show correlation with clinicopathologic characteristics, including patient outcome. Low expression of Bax was significantly correlated with lack of clinical complete response (P = 0.023). Low expression of Bax was also associated with poor OS (median, 8 months versus 16 months; P = 0.0008) in univariate analysis. In multivariate analysis, low expression of Bax was the most significant independent predictor of poor OS (P = 0.009), followed by low dose intensity of cisplatin and lack of clinical complete response. Conclusions: Low expression of Bax was significantly associated with the poor survival of patients with locally advanced esophageal cancer treated with chemoradiotherapy using 5-fluorouracil and cisplatin. Immunohistochemical staining for Bax with a pretreatment biopsy specimen might be useful to select the optimal treatment options for these patients.

Expression of Bcl-2 predicts outcome in locally advanced non-small cell lung cancer patients treated with cisplatin-based concurrent chemoradiotherapy

BACKGROUND Platinum-based concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced unresectable non-small cell lung cancer (NSCLC). The determination of parameters that may predict the result of the treatment has strong clinical implications. PATIENTS AND METHODS Pretreatment tumor biopsy specimens from 39 patients with locally advanced NSCLC (stage IIIA: 5, stage IIIB: 34) were analyzed for p53, Bcl-2, Bax and ERCC1 expression by immunohistochemistry. All patients were treated with cisplatin-based CCRT. Twenty-four patients received induction chemotherapy followed by CCRT (60Gy/30 fractions, 6mg/m(2) of cisplatin daily). The most commonly administered induction chemotherapy regimen was VIP (etoposide, ifosfamide, cisplatin; 20 patients). Fifteen patients received the same CCRT without induction chemotherapy. RESULTS High expression of p53, Bcl-2, Bax and ERCC1 was observed in 15 (38%), 19 (49%), 17 (44%) and 12 (31%) patients, respectively. High expression of Bcl-2 was significantly associated with longer survival duration (20 months vs. 9 months, P=0.008) and better response to the treatment (74% vs. 30%, P=0.01). In multivariate analysis, Bcl-2 expression was the only significant independent prognostic factor of overall survival (P=0.007) among the pretreatment patients characteristics. CONCLUSIONS High expression of Bcl-2 may be a useful prognostic factor in locally advanced NSCLC patients treated with cisplatin-based CCRT.

Helicobacter pylori infection as an independent prognostic factor for locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection

A few studies reported the association between negative Helicobacter pylori infection and poor clinical outcome in resected gastric cancer patients. We investigated the H. pylori infection status and its association with the clinical outcome in 274 locally advanced gastric cancer patients (American Joint Committee on Cancer stage IB: 25, II: 82, IIIA: 80, IIIB: 39 and IV: 48) who underwent adjuvant chemotherapy after curative resection (≥D2 dissection). H. pylori infection status in hematoxylin and eosin stained corporal and antral mucosa of non‐tumor tissue was graded according to the updated Sydney System and categorized as H. pylori negative (normal or mild infection) and H. pylori positive (moderate or marked infection). Eighty‐one patients received 5‐fluorouracil (5‐FU) and doxorubicin‐based chemotherapy, while 193 patients underwent 5‐FU, mitomycin‐C and polysaccharide‐K chemotherapy. The median follow‐up duration of survivors was 144 (120–184) months. In univariate analysis, patients with H. pylori negative status (108 patients) demonstrated significantly poor 10‐year overall survival (OS) compared to those with H. pylori‐positive status (166 patients; 21.3% vs. 71.1%, p < 0.0001). H. pylori negative status was associated with poor outcome in all stages except stage IIIB. In multivariate analysis, H. pylori‐negative status was the most significant independent prognostic factor of poor OS (hazard ratio: 3.45, 95% confidence interval: 2.43–4.89, p < 0.0001) followed by old age (>54 years, p < 0.0001), advanced stage (stage III or IV, p = 0.001), and Borrmann type IV (p = 0.027). H. pylori infection status seems to have strong prognostic significance in locally advanced gastric cancer. H. pylori‐negative patients may need careful follow‐up after curative resection.

Chemotherapy-related amenorrhea in premenopausal women with breast cancer.

Objective: To report the incidence of chemotherapy-related amenorrhea (CRA) from chemotherapy with/without adjuvant endocrine therapy in premenopausal women with breast cancer and to analyze the related factors. Design: From January 2000 to August 2006, 326 premenopausal women (≤50 y old) who completed chemotherapy were available for analysis. The CRA definitional criterion in this study was no menstruation for 6 months in a woman who was premenopausal at diagnosis. As risk factors for CRA, womans age, the type of chemotherapy regimen, adjuvant endocrine therapy use, and body mass index were evaluated. Results: The median age was 42 years (range, 22-50 y). The median follow-up period was 37 months (range, 12-80 mo). Women were divided into two groups by age at diagnosis: 128 women in group 1 (less than 40 years old) and 198 women in group 2 (age ≥40 y). CRA occurred in a total of 223 (68%) women: 43% in group 1 and 85% in group 2 (P < 0.001). Despite CRA, 14% resumed menstruation: 24% in group 1 and 11% in group 2. Another 40 (12%) women had less than 6 months of menstruation interruption. Permanent CRA was related with age at diagnosis and use of adjuvant endocrine therapy (P < 0.05). In this study, there were four pregnancies, two of which resulted in therapeutic abortion due to ongoing chemotherapy. Conclusions: This study confirmed that the rate of CRA depends on age at diagnosis and the use of adjuvant endocrine therapy. It is essential to inform young women of reproductive age of the possibility of amenorrhea or resumption of menstruation and contraceptive options.

High expression of excision repair cross-complementation group1 protein predicts poor outcome in patients with nasopharyngeal cancer

We evaluated the prognostic significance of excision repair cross-complementation group 1 protein (ERCC1) and thymidylate synthase (TS) in patients with nasopharyngeal cancer (NPC) treated with concurrent chemoradiotherapy (CCRT). Pre-treatment tumor biopsy specimens from 41 patients with locally advanced NPC (stage I: 1, II: 10, III: 9, IV: 21 patients) were analyzed for ERCC1 and TS expression by immunohistochemistry. All patients were treated with one cycle of induction chemotherapy (5-fluorouracil 1000 mg/m(2)/day and cisplatin 20mg/m(2)/day, days 1-4) followed by CCRT starting on day 22. CCRT consisted of radiotherapy (70 Gy/35 fractions for 7 weeks) with cisplatin 20mg/m(2)/day for 4 days on weeks 1, 4, and 7 of radiotherapy. High expression of ERCC1 and TS was observed in 25 (60%) and 21 (51%) patients, respectively. High expression of ERCC1 was associated with WHO type 1 or 2 histology (p=0.045). With a median follow-up duration of 106 months (32-152 months) in survivors, the 5-year overall survival (OS) of all patients was 53%. In univariate analysis, 5-year OS (73% versus 39%, p=0.005) was significantly inferior in patients with high expression of ERCC1, while high expression of TS was not correlated with patient outcome. In multivariate analysis, high expression of ERCC1 was a significant independent prognostic factor for poor OS (p=0.029) along with WHO type 1 or 2 histology. High expression of ERCC1 protein may be a useful prognostic factor for poor outcome in patients with locally advanced NPC treated with CCRT.