Quantitative Multiplexed Proteomics Could Assist Therapeutic Decision Making in Non-Small Cell Lung Cancer Patients with Ambiguous ALK Test Results.

Therapeutic guidance in non-small cell lung cancer (NSCLC) tumors that are positive for anaplastic lymphoma kinase (ALK) fluorescent in situ hybridization (FISH), but negative for ALK immunohistochemistry, is still challenging. Parallel routine screening of 4588 NSCLC cases identified 22 discordant cases. We rechecked these samples using ALK antibodies and selected reaction monitoring (SRM) quantitative multiplexed proteomics screening multiple protein targets, including ALK and MET for the ALK tyrosine kinase inhibitor (TKI), and FR-alpha, hENT1, RRM1, TUBB3, ERCC1, and XRCC1 for chemotherapy. The presence of ALK (31.8%), MET (36.4%), FR-alpha (72.7%), hENT1 (18.2%), RRM1 (31.8%), TUBB3 (72.9%), ERCC1 (4.5%), and a low level of XRCC1 (54.4%) correlated with clinical outcomes. SRM was more sensitive than the ALK D5F3 assay. Among the eight cases receiving ALK TKI, four cases with ALK or MET detected by SRM had complete or partial responses, whereas four cases without ALK or MET showed progression. Twenty-seven treatment outcomes from 20 cases were assessed and cases expressing more than half of the specific predictive proteins were sensitive to matching therapeutic agents and showed longer progression-free survival than the other cases (p < 0.001). SRM showed a potential role in therapeutic decision making in NSCLC patients with ambiguous ALK test results.

The effect of adjuvant chemotherapy and early tumor regression on the outcome of nasopharyngeal cancer patients treated with concurrent chemoradiotherapy.

OBJECTIVES: We assessed the role of adjuvant chemotherapy (ACT) in patients with advanced nasopharyngeal carcinoma treated with concurrent chemoradiotherapy (CCRT) and investigated the prognostic factors for recurrence and survival. MATERIALS AND METHODS: Between January 2008 and January 2018, 88 non-metastatic nasopharyngeal carcinoma patients treated with CCRT and with or without ACT in two institutions were retrospectively reviewed. The initial tumor response evaluation was performed 1 month after CCRT completion. Survival analysis was performed for factors such as initial tumor regression, ACT and other clinical factors. Subgroup analysis was performed for the four-group categorized according to tumor regression and ACT (CR with/without ACT, non-CR with/without ACT). RESULTS: Complete response (CR) 1 month after CCRT was a favorable prognosticator for progression-free survival (PFS) (hazard ratio [HR] 3.16, 95% confidence interval [CI] 1.02-9.85, p = 0.046) and overall survival (OS) (HR 3.19, 95% CI 1.14-8.93, p = 0.027). Also, ACT was an independent factor for PFS (HR 0.38, 95% CI 0.15-0.98, p = 0.047) and OS (HR 0.37, 95% CI 0.13-0.99, p = 0.047). In subgroup analysis, the CR after CCRT followed by ACT group showed significantly higher locoregional recurrence-free survival (p = 0.02), OS (p = 0.003), distant-metastasis free survival (p = 0.07), and PFS (p = 0.01) than the other three groups. CONCLUSION: Tumor regression 1 month after CCRT, and administration of ACT identified as an independent prognosticator for PFS and OS in this study. Even patients who show early tumor regression after CCRT may benefit from ACT. Further randomized trials should define the role of ACT in patients with nasopharyngeal cancer who achieved CR after CCRT.

Real-World Experience of Nivolumab in Non-small Cell Lung Cancer in Korea.

PURPOSE: The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti-programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. MATERIALS AND METHODS: Previously treated patients with advanced nonsquamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. RESULTS: Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. CONCLUSION: This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.

Upfront radiosurgery plus targeted agents followed by active brain control using radiosurgery delays neurological death in non-small cell lung cancer with brain metastasis.

The role of radiosurgery has become further accentuated in the era of targeted agents (TA). Thus, the neurologic outcome of radiosurgery in brain metastasis (BM) of non-small cell lung cancer (NSCLC) was reviewed. We analyzed 135 patients with BM of NSCLC who were administered Cyberknife radiosurgery (CKRS) as either initial or salvage therapy. We evaluated local failure (LF), intracranial failure (IF), and neurological death (ND) due to BM. Primary outcome was neurological death-free survival (NDFS). Median follow-up was 16.2 months. Median CKRS dose of 22 Gy was administered to median 2 targets per patient. Among 99 deaths, 14 (14%) were ND. Upfront treatment for BM included CKRS alone in 85 patients (63%), CKRS + TA in 26 patients (19%), and WBRT in 24 patients (18%). No patients or tumor related factors were associated with ND. However, the type of upfront treatment for BM was significantly associated with ND [HR 0.07 (95% CI 0.01-0.57) for CKRS + TA, HR 0.56 (95% CI 0.19-1.68) for CKRS alone] compared with the WBRT group (P = 0.01). The 2-year NDFS rates for the CKRS + TA, CRKS alone, and WBRT groups were 94%, 87%, and 78%, respectively (P = 0.03). Upfront CKRS showed significantly higher 2-year LF-free survival rate (P < 0.01). IF rate was insignificantly lower in the WBRT group compared with CKRS group (P = 0.38). Upfront CKRS + TA was associated with the best neurological outcome with high NDFS. Active brain control by early delivery of radiosurgery could achieve better neurological outcome in NSCLC with BM.

High-Dose Thoracic Re-irradiation of Lung Cancer Using Highly Conformal Radiotherapy Is Effective with Acceptable Toxicity.

PURPOSE: Thoracic re-irradiation (re-RT) of lung cancer has been challenged by the tolerance doses of normal tissues. We retrospectively analyzed local control, overall survival (OS) and toxicity after thoracic re-RT using highly conformal radiotherapy, such as intensity modulated radiotherapy and stereotactic body radiotherapy. MATERIALS AND METHODS: Thirty-one patients who received high-dose thoracic re-RT were analyzed. Doses were recalculated to determine biologically equivalent doses. The median interval to re-RT was 15.1 months (range, 4.4 to 56.3 months), the median initial dose was 79.2 Gy10 (range, 51.75 to 150 Gy10), and the median re-RT dose was 68.8 Gy10 (range, 43.2 to 132 Gy10). RESULTS: Eighteen (58.1%) and eleven (35.5%) patients showed loco-regional recurrence and distant metastasis, respectively, after 17.4 months of median follow-up. The 1-year and 2-year local control rates were 60.2% and 43.7%, respectively. The median loco-regional recurrence-free-survival (LRFS) was 15.4 months, and the median OS was 20.4 months. The cumulative and re-RT biologically equivalent dose for α/ß=10 (BED10) doses were the most significant prognostic factors. Cumulative BED10 ≥145 Gy10 and re-RT BED10≥68.7 Gy10 were significantly associated with longer OS (p=0.029 and p=0.012, respectively) and LRFS (p=0.003 and p=0.000, respectively). The most frequent acute toxicity was grade 1-2 pulmonary toxicity (41.9%). No acute grade 3 or higher toxicities occurred. CONCLUSION: Our results show that high-dose thoracic re-RT of lung cancer can be safely delivered using highly conformal radiotherapy with favorable survival and acceptable toxicity. An optimal strategy to select patients who would benefit from re-RT is crucial in extending the indications and improving the efficacy with a sufficiently high dose.

Intracranial control and survival outcome of tyrosine kinase inhibitor (TKI) alone versus TKI plus radiotherapy for brain metastasis of epidermal growth factor receptor-mutant non-small cell lung cancer.

INTRODUCTION: The efficacy of tyrosine kinase inhibitors (TKIs) with and without radiotherapy (RT) has not been determined in patients with brain metastases from epidermal growth factor receptor-mutant TKI naïve non-small cell lung cancer (NSCLC). METHODS: Between 2008 and 2016, 586 patients were diagnosed with NSCLC and treated with TKIs at a hospital in Seoul, South Korea; 81 of these patients met the eligibility criteria for our study. Outcomes analyzed included intracranial progression (ICP), neurological death, and overall survival (OS). RESULTS: The 2-year cumulative incidence of ICP was 36.5% in the TKI plus RT group and 62.2% in the TKI alone group (P = 0.006). The chronological pattern analysis indicated that 64.3% of ICP developed within 12 months of the start of TKI treatment in the TKI alone group. The multivariate analysis revealed that treatment group (P = 0.003) and duration of TKI treatment ≤ 12 months (P < 0.001) were significantly associated with ICP. However, no significant differences were observed in the 2-year OS rate (P = 0.267) or the 2-year cumulative incidence of neurological death (P = 0.740). CONCLUSIONS: Cumulative incidence of ICP was significantly lower with TKI plus RT than with TKI alone; however, there was no significant difference in OS or neurological death. Deferring brain RT may not compromise neurologic and survival outcome in selected patients, but close magnetic resonance imaging follow-up is recommended for patients who defer brain RT.

Overexpression of YAP1 in EGFR mutant lung adenocarcinoma prior to tyrosine kinase inhibitor therapy is associated with poor survival.

EGFR tyrosine kinase inhibitor (EGFR TKI) is approved as first-line treatment for advanced-stage EGFR mutant lung adenocarcinoma (LADC). Yes-associated protein 1 (YAP1), a main effector of the Hippo pathway, is associated with adverse prognosis and disruption of EGFR TKI modulation of non-small cell lung cancer. In this study, we demonstrated a prognostic role of YAP1 in EGFR mutant LADC and efficacy of EGFR TKI therapy. A total of 63 patients, including 41 with paired lung cancer specimens before and after EGFR TKI therapy and 22 with non-paired lung cancer specimens prior to EGFR TKI, were enrolled for examination. Expression of YAP1 protein was evaluated using immunohistochemistry. Fifteen paired cases (36.6%) with high nuclear YAP1 expression were detected in the pre-EGFR TKI LADC group and 21 paired cases (52.5%) after treatment with EGFR TKI. Nuclear YAP1 expression was significantly upregulated after EGFR TKI therapy (P = .002). Fifteen paired cases with high nuclear YAP1 expression before EGFR TKI LADCs showed poorer overall survival (OS) (P = .023) and progression-free survival (PFS) (P = .041). Among the 63 patients under study, those with high nuclear YAP1 expression before EGFR TKI showed shorter OS (P = .038) and PFS (P < .001). High nuclear YAP1 expression in cases with acquired EGFR exon 20 T790 M mutant LADCs showed poorer OS (P < .001). We demonstrated that YAP1 burden before clinical application of EGFR TKI plays a crucial role in prognosis of EGFR mutant LADC treated using EGFR TKI.

Efficacy and safety of oxycodone/naloxone as add-on therapy to gabapentin or pregabalin for the management of chemotherapy-induced peripheral neuropathy in Korea.

AIMS: To investigate the efficacy and safety of oxycodone/naloxone in patients with chemotherapy-induced peripheral neuropathy (CIPN) inadequately controlled with pregabalin or gabapentin. METHODS: This 4-week, multicenter, interventional, single-arm phase IV study included 72 Korean patients with CIPN inadequately controlled with pregabalin or gabapentin (Numeric Rating Scale 0-10; NRS ≥4 at baseline). In addition to pregabalin or gabapentin at existing doses, patients received 20/10 mg/day oxycodone/naloxone (up-titrated to 80/40 mg/day as needed). The primary endpoint was change in NRS score after 4 weeks. Secondary endpoints included Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) scores and safety assessments. RESULTS: The mean ± standard deviation (SD) dose of oxycodone/naloxone was 23.3 ± 7.5 mg/day. At week 4, NRS score reduction was 1.29 ± 1.84 points (21.4% reduction; P < 0.0001). Patients on taxane-based chemotherapy experienced a significantly smaller mean change in NRS score at week 4 compared to patients on other chemotherapy (-0.63 ± 1.54 [n = 30] vs. -1.83 ± 1.00 [n = 36]; P = 0.0072). Although there were no significant changes in FACT/GOG-NTX total scores, improvements were observed in the neurotoxicity subscale measuring numbness/tingling of hands (mean ± SD change: -0.27 ± 1.04; P = 0.0427) and feet (-0.60 ± 1.09; P < 0.0001). Forty-two (58.3%) patients reported adverse events. There were no clinically significant changes in laboratory tests or vital signs. CONCLUSION: Oxycodone/naloxone added to pregabalin or gabapentin provided additional pain relief and symptom control in Korean patients with CIPN, without clinically significant safety concerns.

Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort.

PURPOSE: Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes. MATERIALS AND METHODS: Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes. RESULTS: A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥ 5) were independent poor prognostic factors by multivariate analysis. CONCLUSION: In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.

Soft Tissue Necrosis in Head and Neck Cancer Patients After Transoral Robotic Surgery or Wide Excision With Primary Closure Followed by Radiation Therapy.

Risk factors were evaluated for surgical bed soft tissue necrosis (STN) in head and neck cancer patients treated with postoperative radiation therapy (PORT) after transoral robotic surgery (TORS) or wide excision with primary closure. Sixty-seven patients were evaluated. STN was defined as ulceration and necrosis of the surgical bed or persistently unhealed high-grade acute mucositis with pain after PORT. The median RT dose of primary site was 63.6 Gy (range, 45-67.15 Gy) with 2 Gy/fx (range 1.8-2.2 Gy/fx). Total 41 patients (61.2%) were treated with concurrent chemoradiotherapy. The median follow-up period was 26 months. STN was diagnosed in 13 patients (19.4%). Most of the patients were treated with oral steroids, antibiotics, and analgesics and the lesions were eventually improved (median of 6 months after PORT). STN did not influence local control. A depth of invasion (DOI > 1.4 cm, odds ratio [OR] 14.04, p = 0.004) and maximum dose/fraction (CTVpmax/fx > 2.3 Gy, OR 6.344, p = 0.043) and grade 3 acute mucositis (OR 6.090, p = 0.054) were related to STN. The 12 (23.5%) of 51 oropharyngeal cancer patients presented STN, and the risk factors were DOI > 1.2 cm (OR 21.499, P = 0.005), CTVpmax/fx > 2.3 Gy (OR 12.972, P = 0.021) and grade 3 acute mucositis (OR 10.537, P = 0.052). Patients treated with TORS or WE with primary closure followed by PORT had a high risk of surgical bed STN. STN risk factors included DOI (>1.2-1.4 cm) and CTVpmax/fx (>2.3 Gy). Radiation therapy after TORS must be carefully designed to prevent STN.

Interstitial Lung Change in Pre-radiation Therapy Computed Tomography Is a Risk Factor for Severe Radiation Pneumonitis.

PURPOSE: We examined clinical and dosimetric factors as predictors of symptomatic radiation pneumonitis (RP) in lung cancer patients and evaluated the relationship between interstitial lung changes in the pre-radiotherapy (RT) computed tomography (CT) and symptomatic RP. MATERIALS AND METHODS: Medical records and dose volume histogram data of 60 lung cancer patients from August 2005 to July 2006 were analyzed. All patients were treated with three dimensional (3D) conformal RT of median 56.9 Gy. We assessed the association of symptomatic RP with clinical and dosimetric factors. RESULTS: With a median follow-up of 15.5 months (range, 6.1 to 40.9 months), Radiation Therapy Oncology Group grade ≥ 2 RP was observed in 14 patients (23.3%). Five patients (8.3%) died from RP. The interstitial changes in the pre-RT chest CT, mean lung dose (MLD), and V30 significantly predicted RP in multivariable analysis (p=0.009, p < 0.001, and p < 0.001, respectively). MLD, V20, V30, and normal tissue complication probability normal tissue complication probability (NTCP) were associated with the RP grade but less so for grade 5 RP. The risk of RP grade ≥ 2, ≥ 3, or ≥ 4 was higher in the patients with interstitial lung change (grade 2, 15.6% to 46.7%, p=0.03; grade 3, 4.4% to 40%, p=0.002; grade 4, 4.4% to 33.3%, p=0.008). Four of the grade 5 RP patients had diffuse interstitial change in pre-RT CT and received chemoradiotherapy. CONCLUSION: Our study identified diffuse interstitial disease as a significant clinical risk for RP, particularly fatal RP. We showed the usefulness of MLD, V20, V30, and NTCP in predicting the incidence and severity of RP.

The single institutional outcome of postoperative radiotherapy and concurrent chemoradiotherapy in resected non-small cell lung cancer.

PURPOSE: This study was conducted to observe the outcomes of postoperative radiotherapy (PORT) with or without concurrent chemotherapy in resected non-small cell lung cancer (NSCLC) in single institution. MATERIALS AND METHODS: From 2002 to 2013, 78 patients diagnosed with NSCLC after curative resection were treated with radiotherapy alone (RT, n = 48) or concurrent chemoradiation (CCRT, n = 30). The indications of adjuvant radiation therapy were N2 node positive (n = 31), close or involved resection margin (n = 28), or gross residual disease due to incomplete resection (n = 19). The median radiation dose was 57.6 Gy (range, 29.9 to 66 Gy). RESULTS: Median survival time was 33.7 months (range, 4.4 to 140.3 months). The 5-year overall survival (OS) rate was 49.5% (RT 46% vs. CCRT 55.2%; p = 0.731). The 3-year disease-free survival rate was 45.5% (RT 39.4% vs. CCRT 55.3%; p = 0.130). The 3-year local control rate was 68.1% (RT 64.4% vs. CCRT 77.7%; p = 0.165). The 3-year DMFS rate was 56.1% (RT 52.6% vs. CCRT 61.7%; p = 0.314). In multivariate analysis, age ≥66 years and pathologic stage III were significant poor prognostic factors for OS. Treatment failure occurred in 40 patients. Four patients had radiologically confirmed grade 3 radiation pneumonitis. CONCLUSION: In NSCLC, adjuvant RT or CCRT after curative surgery is a safe and feasible modality of treatment. OS gain was seen in patients less than 66 years. Postoperative CCRT showed a propensity of achieving better local control and improved disease-free survival compared to RT alone according to our data.

Prognostic significance of expression of VEGF and Cox-2 in nasopharyngeal carcinoma and its association with expression of C-erbB2 and EGFR.

BACKGROUND AND OBJECTIVES: This study evaluated several tumor angiogenesis-related markers to examine their expression pattern and relation to clinicopathologic implications of nasopharyngeal carcinoma. METHODS: Paraffin sections from 69 nasopharyngeal carcinomas obtained before radiotherapy were prepared. The expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (Cox-2), C-erbB2, and epidermal growth factor receptor (EGFR) were investigated by immunohistochemistry and then correlated with various clinicopathologic parameters. RESULTS: VEGF was inversely correlated with C-erbB2 (P = 0.036). In survival analysis, high mitosis (≥5/10 high power field) was significantly associated with worse relapse-free survival in univariate analysis (P = 0.048) but not in multivariate analysis (P = 0.153). High stage, high mitotic rate, absence of VEGF, and presence of Cox-2 were associated with worse survival in both univariate analysis (P = 0.002, P = 0.038, P = 0.044, and P = 0.028, respectively) and multivariate analysis (P = 0.007, P = 0.036, P = 0.047, and P = 0.004, respectively). CONCLUSIONS: Absence of VEGF is a useful indicator of poor prognosis in addition to Cox-2 expression, high stage, and high mitosis.

Erlotinib monotherapy for stage IIIB/IV non-small cell lung cancer: a multicenter trial by the Korean Cancer Study Group.

BACKGROUND: Erlotinib (Tarceva, OSI Pharmaceuticals, Melville, NY) is an oral, epidermal growth factor receptor tyrosine kinase inhibitor that has antitumor activity and good tolerability in non-small cell lung cancer (NSCLC). In particular, higher response rates have been reported in Asian patients than in Western patients. The aim of this study conducted by the Korean Cancer Study Group was to evaluate the efficacy and tolerability of erlotinib monotherapy as a palliative treatment for advanced NSCLC patients in Korea. PATIENTS AND METHODS: Patients with histologically or cytologically confirmed stage IIIB or IV NSCLC including recurrent or metastatic disease, with performance status from 0 to 3, were eligible either if they had received any anticancer treatment except epidermal growth factor receptor inhibitors or if they were unsuitable for chemotherapy because of poor performance status. Enrolled patients were treated with oral erlotinib at a dose of 150 mg daily until disease progression or development of intolerable toxicity. RESULTS: A total of 120 patients were enrolled between January 2005 and May 2006. Forty-four patients (36.7%) were female and 72 patients were current or former smoker. Fifty percent of patients had received one prior palliative chemotherapy regimens and 34.2% had two or more prior palliative regimens. The overall tumor response rate was 24.2% (95% confidence interval [CI], 16.8-32.8%) with 4 complete responses and 25 partial responses, and the disease control rate was 56.7%. The favorable clinical variables for tumor response were female (P = 0.001), never smokers (P = 0.041), and adenocarcinoma (P = 0.001). The most common adverse event was skin rash (78% of which grade 3 or 4 skin rash occurred in 13.3% of the patients). With a median follow-up of 23.6 months, the median time to progression was 2.7 months (95% CI, 2.2-3.2), and the median overall survival was 12.9 months (95% CI, 6.9-18.8). By multivariate analysis, female and development of skin rash were significantly associated with longer time to progression and overall survival. CONCLUSION: Erlotinib monotherapy showed significant antitumor activity and an acceptable tolerability profile as a palliative treatment in advanced NSCLC patients in Korea, especially in females, never smokers, and patients with adenocarcinoma histology.

Are there any ethnic differences in molecular predictors of erlotinib efficacy in advanced non-small cell lung cancer?

PURPOSE: This study investigated possible molecular predictors of outcome in Korean patients with advanced non-small cell lung cancer treated with erlotinib. EXPERIMENTAL DESIGN: One hundred and twenty patients received erlotinib and were followed prospectively. Ninety-two tissue samples were analyzed for epidermal growth factor receptor (EGFR) gene mutations (exons 18, 19, and 21), 88 for EGFR gene amplification by real-time PCR, and 75 for EGFR protein expression by immunohistochemistry. RESULTS: The overall tumor response rate was 24.2% (complete response, 4; partial response, 25) with 56.7% of disease control rate. With a median follow-up of 23.6 months, the median time to progression (TTP) was 2.7 months and the median overall survival was 12.9 months. EGFR gene mutations were found in 26.1% (24 of 92), EGFR gene amplification in 40.9% (36 of 88), and EGFR protein expression in 72% (54 of 75). There was a strong association between EGFR gene mutations and gene amplification (gamma = 0.241). Patients with EGFR gene mutations or gene amplification showed both better response rate (58.3% versus 16.2%, P < 0.001; 41.7% versus 17.3%, P = 0.012) and TTP (8.6 versus 2.5 months, P = 0.003; 5.8 versus 1.8 months, P < 0.001) and overall survival (not reached versus 10.8 months, P = 0.023; not reached versus 10.1 months, P = 0.033). By multivariate analysis, EGFR gene mutation was the only significant molecular predictor for TTP (hazard ratio, 0.47; 95% confidence interval, 0.25-0.89). CONCLUSIONS: Our findings indicate that EGFR gene mutation is a more predictive marker for improved TTP than EGFR gene amplification in erlotinib-treated Korean non-small cell lung cancer patients. Prospective studies from diverse ethnic backgrounds are required to determine the exact role of these molecular markers.

Circulating stromal cell derived factor-1alpha (SDF-1alpha) is predictive of distant metastasis in gastric carcinoma.

This study was conducted to investigate the value of the pretreatment circulating stromal cell derived factor-1alpha(SDF-1alpha) in patients with gastric carcinoma. We measured SDF-1alpha serum concentrations and evaluated the relationship between serum SDF-1alpha and serum vascular endothelial growth factor (VEGF) levels and clinical factors in 107 gastric cancer patients. Serum levels of SDF-1alpha and VEGF levels were higher in gastric cancer patients than in controls (p < 0.001). Serum SDF-1alpha levels were higher in metastatic patients than non-metastatic patients (p < 0.001). SDF-1alpha levels were correlated with the presence of distant metastases (r = 0.528; p < 0.001) and correlated with VEGF levels (r = 0.789; p < 0.001). SDF-1alpha might serve as a possible marker for predicting or monitoring distant metastasis in gastric carcinoma.

Preoperative chemoradiotherapy with concomitant small field boost irradiation for locally advanced rectal cancer: a multi-institutional phase II study (KROG 04-01).

PURPOSE: This study was designed to determine the effect of concomitant small field boost irradiation given during preoperative chemoradiotherapy for patients with locally advanced rectal cancer. METHODS: The study prospectively enrolled 38 patients scheduled for preoperative chemoradiotherapy. Pelvic radiotherapy of 43.2 Gy/24 fractions was delivered and boost radiotherapy of 7.2 Gy/12 fractions was concomitantly administered during the latter half of the pelvic radiotherapy treatment period. Two cycles of a bolus 5-fluorouracil and leucovorin injection in the first and fifth weeks of radiotherapy were administered. The median time to surgery after completion of chemoradiotherapy was six weeks. Tumor responses to chemoradiotherapy were assessed by using magnetic resonance volumetry and post-chemoradiotherapy pathology tests to determine tumor downstaging and tumor regression rate. RESULTS: Thirty-six of 38 patients (94.7 percent) underwent the scheduled surgery. The mean tumor volume reduction rate was 70.3 percent, and the clinical response rate was 66.7 percent. The downstaging rates were 41.7 percent for T classification, 85.2 percent for N classification, and 72.2 percent for stage. Tumor regression grades after preoperative chemoradiotherapy were Grade 1 in 5 patients (13.9 percent), Grade 2 in 24 patients (66.7 percent), Grade 3 in 3 patients (8.3 percent), and Grade 4 in 4 patients (11.1 percent). Ten patients (26.3 percent) experienced > or = Grade 3 acute toxicity. CONCLUSIONS: Our data suggest that concomitant boost irradiation does not improve clinical outcomes compared with other published preoperative chemoradiotherapy regimens. In addition, the clinicians choosing to use concomitant small field boost irradiation should be cautious to minimize the risk of unplanned sphincter ablation.

Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma.

Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The presence of serum endostatin in patients with gastric cancer has not been reported. The authors assessed the serum levels of endostatin in patients with gastric carcinoma and evaluated their association with the levels of vascular endothelial growth factor (VEGF) and the clinical outcome. A total of 107 patients with gastric cancer were included in the study. Pretherapeutic serum levels of endostatin and VEGF were measured using an ELISA, and compared with those in 23 healthy controls. The serum levels of endostatin and VEGF were higher in gastric cancer patients than in healthy controls (endostatin, 70.1 +/- 16.6 vs. 52.2 +/- 6.2 ng/mL [p < 0.001]; VEGF, 55.1 +/- 7.6 vs. 32.1 +/- 2.4 ng/mL [p < 0.001]; mean +/- SD). Serum endostatin levels were significantly associated with the presence of distant metastases (r = 0.556, p < 0.001) and VEGF levels (r = 0.335, p < 0.001), but not with the depth of tumor invasion, differentiation, or regional lymph node status. A serum endostatin level above the 75th percentile of the distribution for the patients (79.2 ng/mL) was associated with a poor outcome (last follow-up at 42 months; median survival time, 9 vs. 20 months [log-rank, p = 0.017]; median time to progression, 5 vs. 10 months [log-rank, p = 0.022]) in the patients with metastatic gastric cancer. The results suggest for the first time that an elevated serum level of endostatin at the diagnosis of metastatic gastric cancer could be predictive of a poor outcome.

Irinotecan, continuous 5-fluorouracil, and low dose of leucovorin (modified FOLFIRI) as first line of therapy in recurrent or metastatic colorectal cancer.

BACKGROUND: Irinotecan, in combination with 5-fluorouracil (5-FU) and a high dose of leucovorin (LV), known as FOLFIRI regimen, has shown activity in recurrent or metastatic colorectal cancer. Therefore, we evaluated the efficacy and safety of irinotecan, 5-FU and a low dose of LV (modified FOLFIRI) as a first line of therapy for patients with relapsed or metastatic colorectal cancer. METHODS: Between January 2002 and October 2004, 44 patients with histologically confirmed recurrent or metastatic colorectal cancer were enrolled. The chemotherapy regimen schedule consisted of 180 mg/m2 of irinotecan being administered intravenously (i.v) on Day 1, 400 mg/m2 of 5-FU via i.v bolus with 600 mg/m2 of continuous infusion for 22 hrs on both Day 1 and 2, and 20 mg/m2 of leucovorin on both Day 1 and 2 , repeated every two weeks. RESULTS: The overall response rate was 47.8%. Of the 40 evaluated patients, one had CR (2.3%) and 20 had PR (46.5%). Toxicities were mild and easily manageable. Three patients experienced 23 episodes of Grade 3/4 leukopenia., Only one patient developed Grade 3/4 diarrhea. None experienced Grade 3/4 thrombocytopenia. CONCLUSION: Modified FOLFIRI with a low dose of LV is an effective and tolerable regimen for patients with recurrent or metastatic colorectal cancer.

Loss of estrogen receptor-alpha expression is associated with hypermethylation near its ATG start codon in gastric cancer cell lines.

The proportion of gastric cancers positive for estrogen receptor (ER)-alpha expression is reported to be between 0-67%, depending upon the study. The role of ER-alpha in gastric carcinogenesis is unclear. The ER-alpha gene is located at chromosome 6q25.1, and the long arm of chromosome 6 has been known as a site with frequent loss of heterozygosity (LOH) in gastric cancer. ER expression is linked to suppression of cell proliferation in vitro. Epigenetic inactivation might explain the loss of ER-alpha gene expression in gastric cancer. Given there is no information available regarding the methylation status of the ER-alpha gene promoter region in gastric cancer, we investigated such methylation in 13 gastric cancer cell lines. Western blot analysis, reverse transcription-polymerase chain reaction (PCR), methylation-specific PCR (MS-PCR) and bisulfite sequencing analyses were used. ER-alpha protein was not detected in any cell line, although ER-alpha mRNA was detected in 1 of 13 gastric cancer cell lines. MS-PCR and bisulfite sequencing showed all 13 gastric cancer cell lines had methylated CpG regions in their ER-alpha gene promoters. In conclusion, inactivation of ER-alpha gene expression in gastric cancer cell lines appears associated with CpG island methylation near the TGA initiation codon of the ER-alpha gene.