Taek-Keun Nam

Inhibition of Tumor Growth and Metastasis by a Combination of Escherichia coli–mediated Cytolytic Therapy and Radiotherapy

We have reported that Escherichia coli K-12 colonizes hypoxic and necrotic tumor regions after intravenous injection into tumor-bearing mice. In this study, we established a novel strategy for cancer therapy using engineered bacteria to enhance the therapeutic effects of radiation. E. coli strain K-12 was engineered to produce cytolysin A (ClyA), and its effects on tumor growth in primary and metastatic tumor models were evaluated. A single treatment with E. coli-expressing ClyA significantly decreased tumor growth rates initially (9 days after treatment); however, the tumors tended to grow thereafter. With only radiotherapy (RT; 21 Gy), the tumor growth rates were retarded, but not the tumor sizes. A combination of therapy with E. coli-expressing ClyA and radiation [a total of 5 x 10(7) colony-forming units (CFU) and 21 Gy] resulted in significant tumor shrinkage and even complete disappearance of tumors in mice with tumors derived from murine CT26 colon cancer. Furthermore, treatment with E. coli-expressing ClyA markedly suppressed metastatic tumor growth and prolonged the survival time in mice. The results described here indicate that therapy with engineered E. coli could significantly improve the results of RT, and could exert a striking inhibitory effect on the development of lung metastasis.

The prognostic significance of tumor human papillomavirus status for patients with anal squamous cell carcinoma treated with combined chemoradiotherapy.

The prognostic relevance of tumor human papillomavirus (HPV) status in anal squamous cell carcinoma (SCC) had not been previously investigated, although its relevance to cervical, head and neck SCC is known. We retrospectively evaluated outcomes in 47 patients with anal SCC treated with combined chemoradiotherapy (CCRT) and determined tumor HPV status by HPV DNA chip method and p16 expression by immunohistochemistry (IHC) from paraffin‐embedded tumor tissues. The median age was 65 years (range, 44–90 years). Sixteen (34%) patients were diagnosed with T stage 3 to 4, and 18 (38%) patients had regional nodal disease (N‐positive). Thirty‐five (75%) patients were HPV positive, and 31 (66%) patients were genotype 16 (HPV16‐positive). Thirty‐nine (83.0%) patients were positive for p16. After median follow‐up of 51.7 months (range, 5.1–136.0 months), HPV16‐positive group had significantly better 4‐year progression‐free survival (PFS, 63.1% vs. 15.6%, p < 0.001) and overall survival (84.6% vs. 39.8%, p = 0.008) than HPV genotype 16 negative (HPV16‐negative) group. Patients with p16‐positive tumor also had a better 4‐year PFS (52.5% vs. 25.0%, p = 0.014) than those with p16‐negative tumor. In multivariate analysis for PFS, N‐positive and HPV16‐negative were independent prognostic factors for shorter PFS. Comparing patterns of failure, time to loco‐regional failure was statistically superior in HPV16‐positive over HPV16‐negative groups (p = 0.006), but time to systemic failure was not different (p = 0.098). Tumor HPV genotype 16 status is a prognostic and predictive factor in anal SCC treated with CCRT, and p16 expression determined by IHC might be advocated as a surrogate biomarker of HPV integration in anal SCC. Further studies are warranted.

Concurrent chemoradiotherapy with S-1 and cisplatin in advanced esophageal cancer

How best to manage advanced esophageal cancer remains unresolved, especially in palliative care. Here, in a pilot study, we evaluated the efficacy and safety of concurrent chemoradiotherapy with S-1 and cisplatin in advanced esophageal cancer. Patients with locally advanced or metastatic squamous cell carcinoma of the esophagus received S-1 and cisplatin at doses of 70 mg/m(2)/day for 14 days and 70 mg/m(2) on day 1, respectively, every 3 weeks. Concurrently, radiotherapy was started at a dose of 200 cGy/day, up to a total of 5400 cGy. After concurrent chemoradiotherapy, additive chemotherapy was repeated up to six cycles. Thirty patients were enrolled in this study; of the 27 in whom efficacy could be evaluated, an objective response rate was seen in 20 (74.1%), including five (18.5%) complete pathologic responses in primary lesions. Improvement of dysphagia was seen in 21 (76%) patients. In patients with stage II or III esophageal cancer, the median progression-free survival and overall survival were 10.6 +/- 0.6 months (95% CI: 9.4-11.8) and 23.0 +/- 5.1 months (95% CI: 13.0-32.9), respectively. In patients with stage IV esophageal cancer, the median progression-free survival and overall survival were 5.4 +/- 1.6 months (95% CI: 2.2-8.6) and 11.6 +/- 1.6 months (95% CI: 8.4-14.8), respectively. The main hematological toxicity was neutropenia, but no neutropenic fever was observed. The major non-hematological toxicities were asthenia and vomiting, mostly of grades 1 and 2. Thus, concurrent chemoradiotherapy with S-1 and cisplatin may be a promising nonsurgical treatment in advanced esophageal cancer.

Preoperative Short-Course Concurrent Chemoradiation Therapy Followed by Delayed Surgery for Locally Advanced Rectal Cancer: A Phase 2 Multicenter Study (KROG 10-01)

PURPOSE A prospective phase 2 multicenter trial was performed to investigate the efficacy and safety of preoperative short-course concurrent chemoradiation therapy (CRT) followed by delayed surgery for patients with locally advanced rectal cancer. METHODS AND MATERIALS Seventy-three patients with cT3-4 rectal cancer were enrolled. Radiation therapy of 25 Gy in 5 fractions was delivered over 5 consecutive days using helical tomotherapy. Concurrent chemotherapy was administered on the same 5 days with intravenous bolus injection of 5-fluorouracil (400 mg/m(2)/day) and leucovorin (20 mg/m(2)/day). After 4 to 8 weeks, total mesorectal excision was performed. The primary endpoint was the pathologic downstaging (ypStage 0-I) rate, and secondary endpoints included tumor regression grade, tumor volume reduction rate, and toxicity. RESULTS Seventy-one patients completed the planned preoperative CRT and surgery. Downstaging occurred in 20 (28.2%) patients, including 1 (1.4%) with a pathologic complete response. Favorable tumor regression (grade 4-3) was observed in 4 (5.6%) patients, and the mean tumor volume reduction rate was 62.5 ± 21.3%. Severe (grade ≥3) treatment toxicities were reported in 27 (38%) patients from CRT until 3 months after surgery. CONCLUSIONS Preoperative short-course concurrent CRT followed by delayed surgery for patients with locally advanced rectal cancer demonstrated poor pathologic responses compared with conventional long-course CRT, and it yielded considerable toxicities despite the use of an advanced radiation therapy technique.

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.

Long-Term Follow-Up of Preoperative Pelvic Radiation Therapy and Concomitant Boost Irradiation in Locally Advanced Rectal Cancer Patients: A Multi-Institutional Phase II Study (KROG 04-01)

PURPOSE To perform a prospective phase II study to investigate the efficacy and safety of preoperative pelvic radiation therapy and concomitant small-field boost irradiation with 5-fluorouracil and leucovorin for 5 weeks in locally advanced rectal cancer patients. METHODS AND MATERIALS Sixty-nine patients with locally advanced, nonmetastatic, mid-to-lower rectal cancer were prospectively enrolled. They had received preoperative chemoradiation therapy and total mesorectal excision. Pelvic radiation therapy of 43.2 Gy in 24 fractions plus concomitant boost radiation therapy of 7.2 Gy in 12 fractions was delivered to the pelvis and tumor bed for 5 weeks. Two cycles of 5-fluorouracil and leucovorin were administered for 3 days in the first and fifth week of radiation therapy. The pathologic response, survival outcome, and treatment toxicity were evaluated for the study endpoints. RESULTS Of 69 patients, 8 (11.6%) had a pathologically complete response. Downstaging rates were 40.5% for T classification and 68.1% for N classification. At the median follow-up of 69 months, 36 patients have been followed up for more than 5 years. The 5-year disease-free survival (DFS) and overall survival rates were 66.0% and 75.3%, respectively. Higher pathologic T (P=.045) and N (P=.032) classification were significant adverse prognostic factors for DFS, and high-grade histology was an adverse prognostic factor for both DFS (P=.025) and overall survival (P=.031) on the multivariate analysis. Fifteen patients (21.7%) experienced grade 3 or 4 acute toxicity, and 7 patients (10.1%) had long-term toxicity. CONCLUSION Preoperative pelvic radiation therapy with concomitant boost irradiation with 5-fluorouracil and leucovorin for 5 weeks showed acceptable acute and long-term toxicities. However, the benefit of concomitant small-field boost irradiation for 5 weeks in rectal cancer patients was not demonstrated beyond conventional irradiation for 6 weeks in terms of tumor response and survival.

Prediction of pathologic staging with magnetic resonance imaging after preoperative chemoradiotherapy in rectal cancer: Pooled analysis of KROG 10-01 and 11-02

BACKGROUND AND PURPOSE The reported overall accuracy of MRI in predicting the pathologic stage of nonirradiated rectal cancer is high. However, the role of MRI in restaging rectal tumors after neoadjuvant CRT is contentious. Thus, we evaluate the accuracy of restaging magnetic resonance imaging (MRI) for rectal cancer patients who receive preoperative chemoradiotherapy (CRT). METHODS AND MATERIALS We analyzed 150 patients with locally advanced rectal cancer (T3-4N0-2) who had received preoperative CRT. Pre-CRT MRI was performed for local tumor and nodal staging. All patients underwent restaging MRI followed by total mesorectal excision after the end of radiotherapy. The primary endpoint of the present study was to estimate the accuracy of post-CRT MRI as compared with pathologic staging. RESULTS Pathologic T classification matched the post-CRT MRI findings in 97 (64.7%) of 150 patients. 36 (24.0%) of 150 patients were overstaged in T classification, and the concordance degree was moderate (k=0.33, p<0.01). Pathologic N classification matched the post-CRI MRI findings in 85 (56.6%) of 150 patients. 54 (36.0%) of 150 patients were overstaged in N classification. 26 patients achieved downstaging (ycT0-2N0) on restaging MRI after CRT. 23 (88.5%) of 26 patients who had been downstaged on MRI after CRT were confirmed on the pathological staging, and the concordance degree was good (k=0.72, p<0.01). CONCLUSIONS Restaging MRI has low accuracy for the prediction of the pathologic T and N classifications in rectal cancer patients who received preoperative CRT. The diagnostic accuracy of restaging MRI is relatively high in rectal cancer patients who achieved clinical downstaging after CRT.

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.