Sung-Ja Ahn

Predictors of the Response to Gefitinib in Refractory Non–Small Cell Lung Cancer

Gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has a response rate of 10% to 20% in refractory non–small cell lung carcinoma. Although female gender, adenocarcinoma, and never having smoked are possible markers of a favorable response, mutations of the EGFR gene have also been reported to be highly significant predictors of response. Seventy patients with relapsed non–small cell lung carcinoma were enrolled in the Expanded Access Program. After the drug became available commercially, 28 more patients were treated with gefitinib. Response evaluations were feasible in 80 patients. Twenty-seven tumor specimens (8 responders and 19 nonresponders) were available for the sequence analysis of the EGFR gene. The response rate was 25% (20/80) and the disease control rate (remission + stable disease) was 47.5% (38/80). The response rate was significantly higher for adenocarcinoma (41.0%) versus non-adenocarcinoma (9.8%, P = 0.001), in those who never smoked (58.8%) versus smokers (15.9%, P < 0.001), and in females (42.1%) versus males (19.7%, P = 0.049). A deletion or mutation of the EGFR gene was found in six of eight responders. Remission was noted in all patients with a mutation, whereas the response rate was 9.5% (2/21) in patients without a mutation (P < 0.001). The predictors of response showed significant correlations with survival and time to progression. In a multivariate logistic analysis, the independent predictors of response were smoking history and adenocarcinoma. Given that 9.5% of smokers and 6.7% of those with non-adenocarcinoma showed a mutation of the EGFR gene, the genetic profile may replace those variables as an independent predictor of a response.

Apoptosis and BCL-2 expression as predictors of survival in radiation-treated non–small-cell lung cancer

OBJECTIVES We assessed the role of apoptosis and the expression of bcl-2, p53, and c-myc oncoproteins in pretreatment histologic specimens as a predictor of response to radiation therapy and survival in non-small-cell lung cancer (NSCLC) patients. METHODS Pretreatment biopsy specimens of 68 patients with NSCLC (62 squamous cell carcinoma, 6 adenocarcinoma) were stained with hematoxylin and eosin. From 5 high-powered fields, the apoptotic index (AI) was calculated as the ratio of apoptotic tumor cells to the total number of tumor cells. Bcl-2, p53, and c-myc oncoprotein expression was detected by immunohistochemical staining. RESULTS Twenty-nine cases showed partial or complete remission, whereas 39 showed no response. AI ranged from 0.2 to 12.0% (mean +/- SD; 4.3 +/- 2.6%, median 4.0%). There was no difference in AI between responders (4.0 +/- 2.3) and nonresponders (4.5 +/- 2.8, p > 0.05). However, in the responders, AI was correlated with the degree of change in tumor volume (r = 0.41, p < 0.05). In an analysis of 53 subjects who survived more than 1 month after the completion of radiation therapy, the patients with a higher AI (n = 27, MST = 22.8 m) survived longer than those with a lower AI (n = 26, MST = 9.2, log-rank, p = 0.03). Patients expressing bcl-2 had poorer survival (n = 22, MST = 6.0 m) than patients without bcl-2 (n = 31, 22.8 m, p < 0.003). According to multivariate analysis, three variables, bcl-2 expression, AI, and response to radiation, were independent prognostic factors for survival. CONCLUSION A low level of spontaneous apoptosis and expression of apoptosis blocking bcl-2 protein in pretreatment histology predict a poor prognosis for radiation-treated NSCLC patients.

Effect of pentoxifylline on radiation response of non-small cell lung cancer: a phase III randomized multicenter trial.

PURPOSES The objectives of this prospective clinical trial were to determine whether pentoxifylline improves the radiation response and survival in patients with non-small cell lung cancer. MATERIALS AND METHODS From July 1993 through October 1994, 64 patients with histologically confirmed Stage I, II and III non-small cell lung cancer were randomly divided into pentoxifylline (Pento)+Radiotherapy (RT) group and RT alone group. Out of the 64 patients, only 47 patients who had measurable tumors on chest X-ray views were analyzed and divided into Pento+RT group (n=27) and RT alone group (n=20). Total tumor dose of 65-70 Gy was delivered as conventional fractionated radiation schedules. Pento was given to the patients 3 x 400 mg/day with a daily dose of 1200 mg during RT. RESULTS Complete response (CR), partial response (PR), and stable in Pento+RT group were three (11%), 13 (48%), and 11 (41%), respectively, as compared with corresponding values of three (15%), 13 (65%), and four (20%) in the RT alone group. The median time to relapse in the Pento+RT group was 11 months which was 2 months longer than for the RT alone group (P>0.05). All the patients in both groups showed lower than or equal to grade 2 dysphagia, odynophagia, pulmonary fibrosis, and pneumonitis. The median survival was 18 months in the Pento+RT group and 7 months in the RT alone group. The 1-year survival rate was 60% in the Pento+RT group and 35% in the RT alone group, the 2-year survival rate was 18% in the Pento+RT group and 12% in the RT alone group. But these differences were not statistically significant (P>0.05). CONCLUSION We concluded that Pento is a modestly effective radiation response modifier and provide benefit in the treatment of non-small cell lung cancer.

Endovascular Stenting as a First Choice for the Palliation of Superior Vena Cava Syndrome

To assess the effectiveness of endovascular stenting for the palliation of superior vena cava (SVC) syndrome, endovascular stent insertion was attempted in 10 patients with symptomatic occlusion of the SVC. All the patients had known malignant disease of the thorax. Eight patients had been treated previously with chemotherapy and radiotherapy (n=5), chemotherapy alone (n=2), or pneumonectomy and radiotherapy (n=1). After developing SVC syndrome, all the patients were stented before receiving any other treatment. After single or multiple endovascular stents were inserted, five of eight patients were treated with chemotherapy and radiotherapy (n=2) or chemotherapy alone (n=3). Resolution of symptoms was achieved in nine patients within 72 hr (90%). In one patient, the symptoms did not disappear until a second intervention. At follow up, symptoms had recurred in two of ten patients (20%) after intervals of 15 and 60 days. Five patients have died from their cancers, although they remained free of symptoms of SVC occlusion until death. In conclusion, endovascular stent insertion is an effective treatment for palliation of SVC syndrome. Endovascular stent insertion can be considered the first choice of treatment, due to the immediate relief of symptoms and excellent sustained symptomatic relief.

Metabolic Response of Lymph Nodes Immediately After RT Is Related With Survival Outcome of Patients With Pelvic Node-Positive Cervical Cancer Using Consecutive [18F]fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography

PURPOSE To evaluate the metabolic response of uterine cervix and pelvic lymph nodes (LNs) using consecutive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) immediately after RT and to correlate survival outcome with the metabolic response. METHODS AND MATERIALS We retrospectively reviewed 48 patients with cervical cancer who had positive pelvic LNs by preradiation therapy (pre-RT) PET/CT. All patients underwent PET/CT scans immediately after RT (inter-RT PET/CT) after median 63 Gy to the gross LNs. The metabolic response of the LNs was assessed quantitatively and semiquantitatively by measurement of the maximal standardized uptake value (SUVmax). RESULTS Classifying the metabolic response of all nodal lesions, 37 patients (77%) had LNs with complete metabolic response on the inter-RT PET/CT (LNCMRi), and 11 patients had a non-LNCMRi, including 4 patients with progressive metabolic disease. The overall 3-year survival rates were 83% for the patients with LNCMRi and 73% for the non-LNCMRi group (P=.038). The disease-free survival for patients with LNCMRi were significantly better than that for the non-LNCMRi group (71% vs 18%, respectively, P<.001). The 3-year distant metastasis-free survival rates were 79% for the patients with LNCMRi and 27% for the non-LNCMRi group (P<.001). There were no statistically significant differences in overall survival (76% vs 86%, respectively, P=.954) and disease-free survival rates (58% vs 61%, respectively, P=.818) between the CMR of primary cervical tumor and the non-CMR groups. CONCLUSIONS The results showed a significant correlation between survival outcome and the interim metabolic response of pelvic LNs. CMR of nodal lesion on inter-RT PET/CT had excellent overall survival, disease-free survival and distant metastasis-free survival rates. This suggested that PET/CT immediately after RT can be a useful tool for the evaluation of the interim response of the LNs and identify a subset of patients with a high risk of recurrence and poor survival in patients with cervical cancer with initial positive LNs.

The metabolic response using 18F-fluorodeoxyglucose-positron emission tomography/computed tomography and the change in the carcinoembryonic antigen level for predicting response to pre-operative chemoradiotherapy in patients with rectal cancer.

BACKGROUND AND PURPOSE To predict tumor regression in pre-operative chemoradiotherapy (CRT) using (18)F-fluorodeoxyglucose-positron emission tomography/computed tomography (PET/CT) and serum carcinoembryonic antigen (CEA) in patients with rectal cancer. MATERIALS AND METHODS The metabolic response of the tumor was assessed by determining the maximal standardized uptake value (SUV(max)), absolute difference (ΔSUV(max)), and SUV reduction ratio (SRR) on pre- and post-CRT PET/CT scans. The serum CEA, absolute difference (ΔCEA), and the CEA reduction ratio (CRR) were also determined. A receiver-operating characteristic (ROC) curve was generated. RESULTS Of all seventy two patients, mean pre- and post-CRT SUV(max) was 14.9 and 5.8, respectively. The mean pre- and post-CRT CEA level was 15.5 ng/ml and 5.4 ng/ml, respectively. Forty-three patients (59.8%) were classified as responders (Dworaks tumor regression grade 3-4) and 36 patients (50%) achieved tumor down-staging. ROC analysis showed that both post-CRT SUV(max) and SRR were predictive factors for responders (p=0.03 and p=0.02, respectively). A threshold of post-CRT SUV(max) was 5.4 and that of SRR was 53.1%. Pre-CRT SUV(max), ΔSUV(max), and all parameters in regard to CEA were not significant in ROC analysis. CONCLUSIONS The post-CRT SUV(max) and SRR are potential factors for predicting tumor response in pre-operative CRT. The patients with lower post-CRT SUV(max) and higher SRR could be expected to achieve maximum tumor regression after pre-operative CRT in this study.

VEGF as a Predictor for Response to Definitive Chemoradiotherapy and COX-2 as a Prognosticator for Survival in Esophageal Squamous Cell Carcinoma

We investigated the patterns of pretreatment expression of the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) by immunohistochemical staining and determined their correlation with treatment response and survival in 44 patients with esophageal squamous cell carcinoma (ESCC) treated with definitive concurrent chemoradiotherapy (CCRT). The definitive CCRT consisted of a median dose of 54 Gy (range: 40.0-68.4 Gy) and two cycles of concurrent administration of mostly 5-fluorouracil + cisplatinum. High expression of EGFR, VEGF, and COX-2 was found in 79.5%, 31.8%, and 38.6%, respectively. The Cox regression analysis for overall survival (OS) showed that both the treatment response and COX-2 expression were significant. The 3-yr OS rates of patients that achieved a complete response and those that did not were 46.7% and 5.3%, respectively (P = 0.006). The logistic regression analysis for treatment response with various parameters showed that only a high expression of VEGF was significantly associated with a complete response. Unlike other well-known studies, higher expression of VEGF was significantly correlated with a complete response to CCRT in this study. However, higher expression of COX-2 was significantly associated with shorter survival. These results suggest that VEGF might be a predictive factor for treatment response and COX-2 a prognostic factor for OS in patients with ESCC after definitive CCRT.

Disease-free survival of patients after surgical resection of non-small cell lung carcinoma and correlation with excision repair cross-complementation group 1 expression and genotype

Background and objective:  Expression of excision repair cross‐complementation group 1 (ERCC1) is recognized as a favourable prognostic marker in patients who have undergone surgical resection of non‐small cell lung cancer (NSCLC). However, in patients treated with adjuvant chemotherapy after surgical resection, ERCC1 correlated with poor prognosis. Class III beta tubulin (TUBB3) is also known to be a predictive marker of the efficacy of treatment with taxanes or vinorelbine.

A study on the reactive ion etching of SiC single crystals using inductively coupled plasma of SF6-based gas mixtures

Inductively coupled plasma reactive ion etching (ICP-RIE) of SiC single crystals using SF6-based gas mixtures was investigated. Mesas with smooth surfaces with vertical sidewalls were obtained, with an etch rate of about 360 nm/min, roughness of about 0.8 nm, and verticality of 85° at optimum conditions. Efforts to increase the etch rate by increasing bias power resulted in a trenching effect. Sloped sidewalls (about 50°) could be obtained by performing RIE (without ICP power) with a photoresist or SiO2 etch mask. Results of various surface characterizations and I-V measurements using an Au Schottky barrier diodes indicated little contamination and/or damage on the etched SiC surfaces.

RESPIRATORY MOTIONAL EFFECT ON CONE-BEAM CT IN LUNG RADIATION SURGERY

The cone-beam CT (CBCT), which is acquired using an on-board imager (OBI) attached to a linear accelerator, is used effectively in the verification of setup accuracy for lung radiation surgery. In this study, the respiratory organ motional effect on the CBCT was evaluated with a properly devised phantom system, and the level of possible error in conditions of a real clinical process was assessed. In a comparison study between the CBCT in static status and CBCT images acquired in 20 different motional cases, we confirmed that the image quality and information of CBCT were degraded, with an increase of motional ranges in the region of inhomogeneous structures. The 4D-CT MIP (50 approximately 55%) for the planning of lung radiation surgery and the 4D-CT MIP (full phase) were compared with CBCT in the various motional cases for the evaluation of the influence of the motional effect on CBCT in the process of the setup error correction. The average ratio of relative difference between plan CT: 4D-CT MIP (50% approximately 55%) and CBCT was 5.79% and between plan CT: 4D-CT MIP (50% approximately 55%) and 4D-CT MIP (full phase) was 42.95% in the phantom study. In the analysis of clinical cases of lung radiation surgery, the gross tumor volumes were compared in each CT image. The average ratio of relative difference between plan CT: 4D-CT MIP (50 approximately 55%) and CBCT was 10.72% and between plan CT: 4D-CT MIP (50 approximately 55%) and 4D-CT MIP (full phase) was 28.19%. These results showed that, although a respiratory organ motional effect on CBCT introduced variation in image quality, the error as a result of this variation could be estimated relatively low in the setup error correction for a gated-lung radiation surgery when the planning was performed in 4D-CT MIP (50 approximately 55%), which already included a related signal of motional effect.