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Radiation-induced lung damage is an important treatment-related toxicity after lung stereotactic ablative radiotherapy (SABR). After implementing a tri-60Co magnetic-resonance image guided system, ViewRayTM, we compared the associated early radiological lung density changes to those associated with a linear accelerator (LINAC). Eight patients treated with the tri-60Co system were matched 1:1 with patients treated with LINAC. Prescription doses were 52 Gy or 60 Gy in four fractions, and lung dose-volumetric parameters were calculated from each planning system. The first two follow-up computed tomography (CT) were co-registered with the planning CT through deformable registration software, and lung density was measured by isodose levels. Tumor size was matched between the two groups, but the planning target volume of LINAC was larger than that of the tri-60Co system (p = 0.036). With regard to clinically relevant dose-volumetric parameters in the lungs, the ipsilateral lung mean dose, V10Gy and V20Gy were significantly poorer in tri-60Co plans compared to LINAC plans (p = 0.012, 0.036, and 0.017, respectively). Increased lung density was not observed in the first follow-up scan compared to the planning scan. A significant change of lung density was shown in the second follow-up scan and there was no meaningful difference between the tri-60Co system and LINAC for all dose regions. In addition, no patient developed clinical radiation pneumonitis until the second follow-up scan. Therefore, there was no significant difference in the early radiological lung damage between the tri-60Co system and LINAC for lung SABR despite of the inferior plan quality of the tri-60Co system compared to that of LINAC. Further studies with a longer follow-up period are needed to confirm our findings.

Objective: To evaluate the effects of recombinant human epidermal growth factor (rhEGF) on proliferation and radiation survival of normal fibroblast and cancer cell lines both in vitro and in vivo. Methods: Using normal fibroblast and cancer cell lines, we evaluated the expression of EGFR, and determined their pro- liferation and survival with rhEGF alone or in combination with radiation. For the combination treatments, we applied 10 nM rhEGF and delivered single radiation doses of 0, 2, 5, and 10 Gy. In the animal study, we introduced EMT-6 cells into BALB/c mice to assay for tumor growth delay. We applied single radiation dose of 10 or 20 Gy, with or without 1.0 mg/Kg of rhEGF, three times a day, for 7 days. Results: In a dose-dependent manner, rhEGF stimulated proliferation of the normal fibroblast, but not the cancer cell lines with low or intermediate expression of EGFR. rhEGF inhibited proliferation of the cancer cell line with the highest EGFR expression. Administration of rhEGF in combination with radiation attenuated the cell killing effect of radiation in normal fibroblast, but it had no effect or even augmented the radiation effect in cancer cell lines. In the animal study, we observed no difference in tumor growth rates when rhEGF was combined with radiation compared to radiation alone. Conclusions: Our results suggested that rhEGF might be useful in preventing and/or treating radiation-induced injury without stimulating tumor growth. Mini-Abstract: rhEGF effectively stimulated proliferation and radiation recovery in normal fibroblasts without promoting the growth of tumor cells. Therefore, it might be useful in preventing and/or treating radiation-induced tissue injury.

Our aim was to evaluate the feasibility and efficacy of intensity-modulated radiation therapy (IMRT) with simultaneous integrated boost (SIB) technique following neoadjuvant chemotherapy for locoregionally advanced nasopharyngeal cancer (NPC).Between April 2004 and December 2006, 25 patients with stage IIB to IVB NPC underwent 3 cycles of neoadjuvant chemotherapy followed by IMRT using SIB technique. Neoadjuvant chemotherapeutic regimens were 5-fluorouracil and cisplatin in 11 patients; docetaxel, 5-fluorouracil, and cisplatin in 8; and paclitaxel and cisplatin in 6. Dose prescription of IMRT was as follows: 67.5 Gy at 2.25 Gy/fraction to postchemotherapy gross tumor, 54 to 60 Gy at 1.8 to 2 Gy/fraction to subclinical disease, and 48 Gy at 1.6 Gy/fraction to elective neck. Seventeen patients received weekly cisplatin during the course of radiation therapy as well.With a median follow-up of 29 months for survivors (range, 14-39), the 3-year local progression-free, regional progression-free, and distant metastasis-free survival rates were 89.6%, 87.2%, and 80.4%, respectively. Treatment was well tolerated despite the grade 3 mucositis (16%) and/or pharyngitis (16%). With follow-up, the frequency of xerostomia decreased. At 3 months after IMRT, the proportions of Radiation Therapy Oncology Group grades 0, 1, and 2 xerostomia were 13%, 38%, and 50%, respectively. At 24 months, the corresponding figures were 36%, 46%, and 18%, respectively.IMRT with SIB technique for locoregionally advanced NPC was feasible and effective regarding locoregional control and development of xerostomia, even after neoadjuvant chemotherapy. Definition of gross tumor volume by postchemotherapy extent of disease was also feasible.

Background Recent researches revealed that class III β-tubulin (TUBB3) is a prognostic marker in various tumors and role of TUBB3 in head and neck squamous cell carcinoma (HNSCC) is not defined yet. We analyzed the significance of TUBB3 expression along with p53 and ERCC1 in locally advanced HNSCC patients receiving cisplatin-based induction chemotherapy. Materials and methods Retrospective review of medical records at Seoul National University Hospital between 1998 and 2007 was carried out. Immunohistochemical stain of TUBB3, p53, and ERCC1 was done in paraffin-embedded tumor tissue. We assessed response to treatment, progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). Results Eighty-five patients with oropharyngeal, hypopharyngeal, and laryngeal cancers received induction chemotherapy with 5-fluorouracil (5-FU) and cisplatin (n = 55), or 5-FU, cisplatin, and docetaxel (Taxotere) (n = 30). Eighty-three received definitive treatment after induction chemotherapy, where 62 received radiotherapy and 21 received surgery. TUBB3-positive patients showed lower response rate than TUBB3-negative patients (69% versus 88%, P = 0.039). Shorter median PFS was observed in TUBB3-positive group (12 versus 47 months, P = 0.001). Shorter median OS was observed in TUBB-positive group not reaching statistical significance (30 versus 59 months, P = 0.072). TUBB3 status significantly influenced CSS (35 months versus not reached, P = 0.017). Positive p53 status was related to poorer OS and CSS. ERCC1 showed no influence on chemotherapy response, PFS, OS, and CSS. Conclusion TUBB3 is a predictive and prognostic marker along with well-known p53 in HNSCC patients receiving cisplatin-based induction chemotherapy. Clinical impact of ERCC1 is not evident in this setting.

Aims and Background To evaluate whether doses or dose rates at International Commission on Radiation Units (ICRU) reference points are of value for predicting risks of late rectal and bladder morbidity in patients with uterine cervical cancer who have undergone external beam radiotherapy and intracavitary irradiation. Methods Late rectal complications and late bladder complications were evaluated in 54 patients who were treated by external beam radiotherapy followed by intracavitary irradiation between January 1996 and December 1999. External beam radiotherapy was delivered in 1.8 Gy daily fractions to a whole pelvis dose of 50.4 Gy followed by intracavitary irradiation at total point A doses ranging from 75 Gy to 85 Gy. Intracavitary irradiation was performed with dose rates of 0.5–0.7 Gy/h to point A in most patients, but 8 patients were treated at a higher dose rate (0.83–1.15 Gy/h) to shorten the hospitalization period. Biologically effective doses for the reference points were calculated using a linear quadratic model. Results Grade 3 rectal and bladder morbidity by Radiation Therapy Oncology Group (RTOG) criteria developed in 4 patients (7.4%) and 1 (1.9%), respectively. An age of >60 years (P = 0.01) and a total dose to the rectal reference point of ≥80 Gy (P = 0.03) were found to be correlated with a higher rate of rectal morbidity. Total dose (≥80 Gy), dose rate (≥0.75 Gy/h), and biologically effective doses (≥135 Gy3) at the bladder reference point were found to be significant factors for the development of late bladder morbidity. By multivariate analysis, age was identified as the only significant factor of late rectal complications, and biologically effective doses at the bladder reference point was the only significant factor of late bladder complications. Conclusions RTOG grade 3 late rectal and bladder morbidity developed in respectively 7.4% and 1.9% of the patients. The significant risk factors for late rectal and bladder morbidity were old age and biologically effective doses at the bladder reference point, respectively.

Objectives: To analyze the impact of neoadjuvant chemotherapy (CT) on the treatment of early-stage nasopharyngeal carcinoma (NPC) as compared with radiotherapy (RT) alone. Methods: We analyzed retrospectively the outcome of 60 previously untreated and histologically confirmed early-stage NPC patients treated with either RT alone or with neoadjuvant CT followed by RT (CT/RT) at the Seoul National University Hospital between 1986 and 2004. Neoadjuvant CT consisted of three cycles with 5-fluourouracil and cisplatin. RT was given to the nasopharynx and neck nodes. The median dose to the primary site, involved nodes, and elective nodes was 70.2 Gy, 63 Gy, and 45 Gy, respectively. According to the 1997 American Joint Committee on Cancer staging system, 9 patients had stage I or IIA disease, and 22 patients had stage IIB disease in the RT group. For the CT/RT group, 8 patients had stage I or IIA disease, and 21 patients had stage IIB disease. The median follow-up for all patients was 124.5 (range, 5–239) months. Results: The 5-year locoregional failure-free (LRFF), distant metastasis-free (DMF), disease-free survival (DFS), and overall survival (OS) rate was 84%, 93%, 81%, and 84% for the RT group and 77%, 86%, 71%, and 79% for the CT/RT group, respectively. There were no significant differences in LRFF (P = .728), DMF (P = .433), DFS (P = .562), and OS (P = .625) rates between the RT and CT/RT groups. Multivariate analysis revealed that delaying RT for more than 81 days was significantly associated with an increased risk of locoregional failure in the subgroup of patients with stage IIB disease (P = .044). Conclusions: In our retrospective analysis, the use of neoadjuvant CT showed no additional benefit to treatment with RT alone. Neoadjuvant CT may cause deleterious effect on stage IIB disease by delaying RT.

Radiotherapy would be the choice of treatment for human cancers, because of high cost-effectiveness. However, a certain population of patients shows a resistance to radiotherapy and recurrence. In an effort to increase the efficacy of radiotherapy, many efforts were driven to find the genes causing the unresponsiveness to ionizing radiation. In this paper, we compared the gene expression profiles of two lung cancer cell lines, H460 and H1299, which showed differential responses to ionizing radiations. Each cell were irradiated at 2 Gy, and harvested after 0, 2, 4, 8, 12 and 24 hours to examine the expressions. Two-way ANOVA analysis on time-series experiments of two cells could select 2863 genes differentially expressed upon ionizing radiation among 32,321 genes in microarray (p＜0.05). We classified these genes into 21 clusters by SOM clustering according to the interaction between cell types and time. Two SOM clusters were enriched with apoptosis-related genes in pathway analysis. One cluster contained higher levels of phosphatidyl inositol 3-phosphate kinase (PI3K) subunits in H1299, radio-resistant cells than H460, radiosensitive cells. TRAIL receptors were expressed in H460 cells while the decoy receptor for TRAIL was expressed in H1299 cells. From these results, we could characterize the differential responsiveness to ionizing radiation according to their differential expressions of apoptosis-related genes, which might be the candidates to increase the power of radiotherapy.

Background. Although meta-analysis showed that survival improved with concurrent chemoradiation in locally advanced head and neck cancer, neoadjuvant chemotherapy is still unique, because it renders curative surgery feasible for marginally resectable head and neck cancer patients. Methods. We reviewed patients with locally advanced head and neck cancer, who had been treated with neoadjuvant chemotherapy between June 1984 and February 2001 at the Seoul National University Hospital. Results. A total of 167 patients were included. After 2 to 3 chemotherapy cycles, either surgery (38 patients) or radiation (104 patients) was conducted. Those who received surgery exhibited better survival than those who received radiation [median survival: not reached vs 33.6 months (95% CI: 22.6–44.7), p = .006]. The 5-year and 10-year survival rates of surgery group were 63.2% and 59.8%. Conclusion. The potential benefit of neoadjuvant chemotherapy with surgery in patients with locally advanced head and neck cancers merits further evaluation in future clinical trials. © 2007 Wiley Periodicals, Inc. Head Neck, 2008

Pre-RT ND in patients with HNSCC undergoing organ preservation treatment is safe, advantageous, poses no additional morbidity owing to the elective neck dissection, and may possibly improve survival outcomes.Establish the role of pre-radiation neck dissection (pre-RT ND) in patients with headneck squamous cell carcinoma (HNSCC) undergoing organ preservation treatment.Fourteen patients with histologically confirmed HNSCC in stages III approximately IV with proven regional metastasis were enrolled in the organ preservation approach incorporating pre-RT ND at a tertiary referral center between May 1998 and August 2004. Site matched patients treated with organ preservation intent in the conventional fashion were used as controls. Data were collected for their diagnosis, management, treatment outcome, and follow up.Disease free survival was significantly better for the pre-RT ND group. There was no significant difference in overall survival, pattern of recurrence, and primary organ preservation rate between the two groups. No significant morbidity owing to neck dissection was noted in patients who underwent neck dissection. Although the delivery of radiation to the primary site was delayed for patients in the pre-RT ND group, it did not influence the major outcomes.

Objectives To evaluate the toxicity and the efficacy of paclitaxel/carboplatin chemoradiotherapy as a definitive treatment for squamous cell cancer of the uterine cervix. Methods From March 2000 to January 2004, 33 patients with squamous cell cancer of the uterine cervix were treated with concurrent chemoradiotherapy including 2 cycles of paclitaxel (135 mg/m2) and carboplatin (area under the time–concentration curve 4.5 mg min/ml) at 4-week interval. Seven patients received adjuvant chemotherapy with the same chemotherapeutic regimen. All patients received external beam radiotherapy with 41.4–51.4 Gy (median 50.4 Gy) to the whole pelvis. Twenty-eight patients received boost irradiation to the cervix by brachytherapy with 25.6–43.3 Gy (median 34.6 Gy) and 5 patients by external beam radiotherapy with 10.8–14.4 Gy (median 14.4 Gy). Results A median follow-up period was 27 months (range: 6–53 months). Acute hematological toxicity of grade 3 or 4 developed in 20 patients (61%), and acute gastrointestinal toxicity of grade 3 developed in 1 patient (3%). Vesicovaginal fistula occurred in 2 patients (6%). All patients achieved objective response (CR 70%, PR 30%) in 2 months after termination of treatment. One patient had a local progression in cervix, and 4 patients developed distant metastases. The 3-year estimated disease-free survival rates for stages I–IIA, IIB, III and IV were 67%, 91%, 88% and 50%, respectively. The 3-year estimated survival rates for stages I–IIA, IIB, III and IV were 89%, 91%, 88% and 50%, respectively. Conclusion Concurrent chemoradiotherapy with paclitaxel and carboplatin is effective to achieve an excellent pelvic control.

Virus-associated malignancies and sarcomatoid cancers correlate with high PD-L1 expression, however, underlying mechanisms remain controversial. We evaluated the correlation between PD-L1 expression and epithelial-mesenchymal transition (EMT) in head and neck squamous cell carcinomas (HNSCC). Tumor tissues from 50 patients with HNSCC were evaluated for PD-L1 by immunohistochemistry, which showed 32 (64.0%) were PD-L1 positive (PD-L1+). Interestingly, PD-L1 expression was significantly associated with EMT (P = 0.010), as assessed by low E-cadherin and high vimentin expression. The overall survival of PD-L1+ patients with EMT features was significantly worse than those without EMT features (P = 0.007). In an independent validation cohort (N = 91), as well as in HNSCC cases of The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia, high PD-L1 expression was also associated with the high probability of an EMT signature, referred from the GEO dataset, GSE4824. Survival analysis confirmed PD-L1+/EMT+ patients had a poorer prognosis than PD-L1+/EMT- patients in the TCGA cohort. PD-L1 positivity can thus be divided into two categories according to the absence or presence of EMT. PD-L1 expression is also independently associated with EMT features in HNSCC.

The purpose of this study was to prospectively evaluate the scintigraphic results on patients who undergo intensity-modulated radiotherapy (IMRT) to investigate the tolerance doses for the salivary glands.Salivary scintigraphy was performed on 35 patients with head and neck cancer before the beginning of radiotherapy (RT), and then at 6 weeks and again at 3 months after the completion of RT. Xerostomia was recorded according to the Radiation Therapy and Oncology Group (RTOG) grade. Salivary function was evaluated by calculating the excretion rate changes (ΔF) for each salivary gland before and after RT.The parotid mean dose was significantly related to parotid ΔF and the submandibular gland mean dose to the submandibular gland ΔF. The parotid mean dose of 23 Gy was best correlated with the RTOG grades. The submandibular gland mean dose significantly related to ΔF ≤-50% and ≤-75% was 42 Gy.The parotid mean dose of 23 Gy and the submandibular gland mean dose of 42 Gy is feasible for salivary function preservation in the IMRT era. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1746-E1755, 2016.

Because of a lack of randomized trials, the role of postoperative radiotherapy (PORT) in thymomas has not been established. This study evaluated the prognostic impact of the adjuvant treatment in surgically resected nonlocalized thymomas.Patients diagnosed between 2000 and 2010 were identified from the Surveillance, Epidemiology, and End Results database (1973-2011 registry). Cases with localized or organ-confined tumors were not included. Propensity-matched analysis was conducted considering baseline characteristics.A total of 529 patients were identified. The median age was 57 years (range, 18-86), and 345 (65%) patients received PORT. Before and after propensity score matching, overall survival (OS; p = 0.018 and 0.008, respectively) and disease-specific survival (DSS; p = 0.007 and 0.008, respectively) were better in the PORT group. In multivariate analyses of the matched population, no receipt of PORT induced poorer OS (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.27-3.09) and DSS (HR, 2.64; 95% CI, 1.32-5.29). Primary tumor extensions of adjacent organs or structures and further contiguous extensions also resulted in worse outcomes (p0.001 and equal to 0.039 for OS; p = 0.006 and 0.009 for DSS, respectively). In the subgroup analyses, PORT was associated with favorable OS in stages III and IV (p = 0.049 and 0.012, respectively) and DSS in stage III (p = 0.005).Regarding the independent prognostic significance of PORT, this population-based analysis demonstrates the survival benefits of PORT in relation to nonlocalized thymomas. We recommend consideration of PORT in the poor prognostic subset of stages III to IV in the contemporary era.

Purpose We investigated whether miR-203 could modulate the radiation sensitivity of glioblastoma (GBM) cells and which target gene(s) could be involved. Methods and Materials Three human malignant glioma (MG) cell lines and normal human astrocytes were transfected with control microRNA, pre-miR-203, or antisense miR-203. Real-time PCR (RT-PCR), clonogenic assays, immunofluorescence, and invasion/migration assays were performed. To predict the target(s), bioinformatics analyses using microRNA target databases were performed. Results Overexpression of miR-203 increased the radiation sensitivity of all 3 human MG cell lines and prolonged radiation-induced γ-H2AX foci formation. Bioinformatics analyses suggested that miR-203 could be involved in post-transcriptional control of DNA repair, PI3K/AKT, SRC, and JAK/STAT3 and the vascular signaling pathway. Western blot analysis validated the fact that miR-203 downregulated ATM, RAD51, SRC, PLD2, PI3K-AKT, JAK-STAT3, VEGF, HIF-1α, and MMP2. Overexpression of miR-203 inhibited invasion and migration potentials, downregulated SLUG and Vimentin, and upregulated Claudin-1 and ZO1. Conclusions These data demonstrate that miR-203 potentially controls DNA damage repair via the PI3K/AKT and JAK/STAT3 pathways and may collectively contribute to the modulation of radiation sensitivity in MG cells by inhibiting DNA damage repair, prosurvival signaling, and epithelium-mesenchyme transition. Taken together, these findings demonstrate that miR-203 could be a target for overcoming the radiation resistance of GBM.

To assess the image quality and dosimetric effects of the Philips orthopaedic metal artefact reduction (OMAR) (Philips Healthcare System, Cleveland, OH) function for reducing metal artefacts on CT images of head and neck (HN) patients.11 patients and a custom-built phantom with metal bead inserts (alumina, titanium, zirconia and chrome) were scanned. The image was reconstructed in two ways: with and without OMAR (OMAR and non-OMAR image). The mean and standard deviation values of CT Hounsfield unit (HU) for selected regions of interest of each case were investigated for both images. Volumetric modulated arc therapy plans were generated for all cases. Gamma analysis of each dose distribution pair in the patient (1%/1 mm criteria) and phantom (2%/2 mm and 3%/3 mm criteria) images was performed. The film measurements in phantom for two metal beads were conducted for evaluating the calculated dose on both OMAR and non-OMAR images.In the OMAR images, noise values were generally reduced, and the mean HU became closer to the reference value (measured from patients without metal implants) in both patient and phantom cases. Although dosimetric difference was insignificant for the eight closed-mouth patients (γ = 99.4 ± 0.5%), there was a large discrepancy in dosimetric calculation between OMAR and non-OMAR images for the three opened-mouth patients (γ = 91.1%, 94.8% and 96.6%). Moreover, the calculated dose on the OMAR image is closer to the real delivered dose on a radiochromic film than was the dose from the non-OMAR image.The OMAR algorithm increases the accuracy of CT HU and reduces the noise such that the entire radiation treatment planning process can be improved, especially for contouring and segmentation.OMAR reconstruction is appropriate for the radiotherapy planning process of HN patients, particularly of patients who use a bite block.

Purpose To investigate the patterns of care for patients with nasopharyngeal carcinoma (NPC) in South Korea. Materials and Methods A multi-institutional retrospective study was performed (Korean Radiation Oncology Group [KROG] 11-06) on a total of 1,445 patients from 15 institutions. Results Of the 1,445 patients, more than half were stages III (39.9%) and IV (35.8%). In addition to patterns of care, we also investigated trends over time with the periods 1988-1993, 1994-2002, and 2003-2011. The frequencies of magnetic resonance imaging and positron emission tomography-computed tomography were markedly increased in the third period compared to previous 2 periods. Concurrent chemoradiation (CCRT) was performed on 894 patients (61.9%), neoadjuvant chemotherapy on 468 patients (32.4%), and adjuvant chemotherapy on 366 patients (25.3%). Of stage II-IV patients, CCRT performed on 78.8% in 2003-2011 compared to 15.0% in 1988-1993. For patients treated with CCRT, cisplatin was the most commonly used agent in 81.3% of patients. Over the periods of time, commonly used radiotherapy (RT) techniques were changed from 2-dimensional RT (1988-1993, 92.5%) to 3-dimensional RT (2003-2011, 35.5%) or intensity-modulated RT (IMRT; 2003-2011, 56.5%). Median RT doses given to primary tumors, high-risk lymphatics, and low-risk lymphatics were 70.0 Gy, 58.1 Gy, and 48.0 Gy, respectively. Adoption of IMRT increased the dose per fraction and escalated total radiation dose. Conclusion Assessment of the patterns of care for NPC patients in South Korea demonstrated that management for NPC including diagnostic imaging, treatment regimen, RT techniques and dose schedule, advanced in accordance with the international guidelines.

To determine a new metric utilizing multileaf collimator (MLC) speeds and accelerations to predict plan delivery accuracy of volumetric modulated arc therapy (VMAT).To verify VMAT delivery accuracy, gamma evaluations, analysis of mechanical parameter difference between plans and log files, and analysis of changes in dose-volumetric parameters between plans and plans reconstructed with log files were performed with 40 VMAT plans. The average proportion of leaf speeds ranging from l to h cm s(-1) (Sl-h and l-h = 0-0.4, 0.4-0.8, 0.8-1.2, 1.2-1.6 and 1.6-2.0), mean and standard deviation of MLC speeds were calculated for each VMAT plan. The same was carried out for accelerations in centimetre per second squared (Al-h and l-h = 0-4, 4-8, 8-12, 12-16 and 16-20). The correlations of those indicators to plan delivery accuracy were analysed with Spearman's correlation coefficient (rs).The S1.2-1.6 and mean acceleration of MLCs showed generally higher correlations to plan delivery accuracy than did others. The highest rs values were observed between S1.2-1.6 and global 1%/2 mm (rs = -0.698 with p 0.001) as well as mean acceleration and global 1%/2 mm (rs = -0.650 with p 0.001). As the proportion of MLC speeds and accelerations0.4 and 4 cm s(-2) increased, the plan delivery accuracy of VMAT decreased.The variations in MLC speeds and accelerations showed considerable correlations to VMAT delivery accuracy.As the MLC speeds and accelerations increased, VMAT delivery accuracy reduced.

The aim of the present study was to suggest potential mechanisms of epidermal growth factor (EGF)-induced cell death and radiosensitization in EGF receptor (EGFR)-overexpressing cancer cell lines.Two EGFR-overexpressing cancer cell lines (AMC-HN3, and A431), one EGFR-null cancer cell line (H520) and normal fibroblasts were cultured with 0.01-1000 nM of recombinant human EGF (rhEGF), and a clonogenic assay was performed. After culturing serum-starved cells with 10 nM rhEGF, the expression patterns of two apoptosis-associated proteins (cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP)) and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway were measured using immunoblotting. The radiosensitizing effect of EGF was also evaluated with a clonogenic assay and phosphorylated H2AX (γH2AX) immunofluorescence.In the clonogenic assay, the number of colonies was decreased in a dose-dependent manner in EGFR-overexpressing cancer cell lines. The expression of cleaved caspase-3 and cleaved PARP was significantly induced in EGFR-overexpressing cancer cell lines. As for the PI3K/AKT/mTOR signaling pathway, EGF paradoxically suppressed the expression of PI3K, AKT and mTOR in a time-dependent manner. As for the radiosensitizing effect, EGF enhanced the radiosensitivity of AMC-HN3 and A431 cells.rhEGF treatment induced cell death in the two EGFR-overexpressing cancer cell lines, and the mode of cell death was apoptosis. Moreover, cell death might be associated with the paradoxical suppression of PI3K/AKT/mTOR signaling pathway. rhEGF in combination with radiation augmented the radiation effect in EGFR-overexpressing cancer cell lines via inhibition of DNA damage repair.

Histone deacetylase inhibitors (HDI) are emerging as potentially useful components of the anticancer armamentarium and as useful tools to dissect mechanistic pathways. HDIs that globally inhibit histone deacetylases (HDAC) have radiosensitizing effects, but the relative contribution of specific HDAC classes remains unclear. Newly characterized HDIs are now available that preferentially inhibit specific HDAC classes, including SK7041 (inhibits class I HDACs) and splitomicin (inhibits class III HDACs). We investigated in human cancer cells the relative radiosensitizations that result from blocking specific HDAC classes. We found that trichostatin A (TSA; inhibitor of both class I and II HDACs) was the most effective radiosensitizer, followed by the class I inhibitor SK7041, whereas splitomicin (inhibitor of class III) had least effect. Interestingly, radiosensitization by TSA in cell lines expressing p53 was more pronounced than in isogenic lines lacking p53. Radiosensitization of cells expressing p53 by TSA was reduced by pifithrin-α, a small-molecule inhibitor of p53. In contrast, the radiosensitization by TSA of cells expressing low levels of p53 was enhanced by transfection of wild-type p53–expressing vector or pretreatment with leptomycin B, an inhibitor of nuclear export that increased intracellular levels of p53. These effects on radiosensitization were respectively muted or not seen in cells treated with SK7041 or splitomicin. To our knowledge, this may be among the first systematic investigations of the comparative anticancer effects of inhibiting specific classes of HDACs, with results suggesting differences in the degrees of radiosensitization, which in some cell lines may be influenced by p53 expression.

This study is a retrospective analysis of stage IB-IIB cervical carcinoma patients who had received postoperative radiotherapy (PORT).Eight hundred patients with stage IB-IIB cervical carcinomas who received PORT after radical hysterectomy and bilateral pelvic lymph node dissection (PLND) between February 1979 and March 2000 were analyzed.The median follow-up duration was 100 months. The 5-year overall survival (OS) and disease-free survival (DFS) rates were 88% and 81%, respectively. One hundred forty-six patients (18%) failed, and 103 of these had distant metastases. Multivariate analysis revealed that pelvic lymph node (LN) metastasis significantly compromised OS, DFS, pelvic failure-free survival (PFFS), and distant failure-free survival (DFFS) (P0.05). Patients with age50 years, deep stromal invasion (DSI), and lymphovascular space invasion (LVSI) were significantly associated with a higher risk of distant metastasis after PORT. The incidences of late rectal, urinary, and small bowel complications of grade 3 or higher were 1.6%, 1.4%, and 1.0%, respectively.PORT achieved good OS and DFS in the patients with risk factors after radical hysterectomy for stage IB-IIB cervical carcinomas. Distant metastasis was the major pattern of treatment failure after PORT. Effective systemic chemotherapy might be a breakthrough in improving the outcome of PORT in patients with cervical carcinomas.

Aim and background The purpose of this study was to analyze the efficacy of neoadjuvant fluorouracil-cisplatin chemotherapy combined with radiotherapy for anal cancer. Methods Fourteen patients with epidermoid carcinoma of the anal canal were analyzed. Treatment consisted of three cycles of 5-fluorouracil (1000 mg/m2 bolus on days 1-5) and cisplatin (60 mg/m2 bolus on day 1) followed by 50.4 Gy to the pelvis and perineum over 5.5 weeks. Both inguinal lymphatics were irradiated with an identical dose schedule. The median follow-up was 78 months. Results Five-year overall survival rate and sphincter preservation rate was 85.1% and 85.7%, respectively. Response to chemoradiotherapy was the only significant factor with univariate analysis (P = 0.031). There were no complications of RTOG grade 3 or higher. Conclusions Neoadjuvant chemotherapy with a cisplatin-based regimen rather than concurrent regimen plus radiotherapy may decrease complications without compromising survival or sphincter preservation.

BACKGROUND The optimal chemotherapy regimen for the treatment of olfactory neuroblastoma has not been clearly defined. The purpose of the current study was to evaluate the efficacy of neoadjuvant chemotherapy with the combination of etoposide, ifosfamide, and cisplatin (VIP) for patients with olfactory neuroblastoma. METHODS Eleven consecutive patients with newly diagnosed olfactory neuroblastoma were treated with etoposide (75 mg/m2), ifosfamide (1000 mg/m2), and cisplatin (20 mg/m2) all administered intravenously on Days 1–5. Cycles were repeated every 21 days. Patients were excluded from analysis if they had previously received surgery or radiotherapy. RESULTS Nine patients achieved objective responses (objective response rate, 82%; 95% confidence interval, 52–95%), which included 2 complete responses and 7 partial responses. The major side effect was hematologic toxicity, with Grade 3/4 neutropenia observed after the receipt of 37% of all cycles and febrile neutropenia observed after the receipt of 2 cycles. All toxic events were reversible, and no chemotherapy-related deaths were documented. The median survival period was 18 months (range, 3–45 months). CONCLUSIONS Neoadjuvant VIP chemotherapy was active in the treatment of olfactory neuroblastoma. Cancer 2004. © 2005 American Cancer Society.

Purpose : The cyclooxygenase (COX)-2 enzyme has been shown to have an important role in carcinogenesis and apoptosis in various types of cancer. The purpose of this study was to evaluate the relationship between local recurrence or distant metastasis and COX-2 expression and apoptosis in cervical cancer patients treated with radical radiotherapy (RT). Methods and Materials : Twenty-two patients who were diagnosed with cervical cancer were enrolled in this study. All patients were treated with radical RT (external beam RT plus brachytherapy) at Seoul National University Hospital. The formalin-fixed, paraffin-embedded tissues of 11 patients who developed local recurrence (n = 3) or distant metastasis (n = 8) were compared with those of other patients who were disease free. Prognostic factors, including tumor size, lymph node metastatic status, and stage, were well balanced between the two groups. COX-2 expression was determined immunohistochemically, and apoptosis was assessed using in situ DNA nick end labeling (TUNEL)-based methods. Results : COX-2 expression was stronger in the local recurrence and distant metastasis patients than in those free of disease. COX-2 expression was shown to have a statistically significant influence on treatment failure by the Mann-Whitney U test (p = 0.015) and the Mantel-Haenszel chi-square test (p = 0.015), but its distribution did not correlate with apoptosis. Among the clinicopathologic factors, including stage, lymph node metastatic status, and tumor size, lymph node metastatic status was found to closely correlate with COX-2 expression by the Mann-Whitney U test (p = 0.045) and Mantel-Haenszel chi-square test (p = 0.065). Conclusion : COX-2 is believed to be one of the important factors associated with lymph node involvement and treatment failure. Our results suggest that inhibiting COX-2 may decrease treatment failure in cervical cancer treated with RT, and that COX-2 inhibitor administration may play an adjuvant role in cervical cancer treatment.

Purpose: To evaluate the effectiveness of whole brain radiotherapy followed by stereotactic radiotherapy for newly diagnosed brain metastasis. Materials and Methods: Thirty-three metastatic brain tumors received radiotherapy to the whole brain and stereotactic radiotherapy in 25 patients. Lung carcinomas were the most common (17/25) primary tumor. The radiation dose was 30 to 40 Gy for the whole brain, with a 12 to 40 Gy boost to the metastatic foci. Survival and local control rates were determined, and the prognostic factors for survival were evaluated. Results: The overall median survival was 15 months and the actuarial survivals at 1- and 2-year were 67% and 31%, respectively. The local tumor control rate was 79%, with a median follow-up period of 9 months (2-36 months). The prognostic factors associated with survival were age, tumor size and the existence of active extracranial metastasis, with the performance status showing marginal significance. No acute or chronic complications were observed in the patients. Conclusion: From our data, cranial radiotherapy followed by stereotactic radiotherapy was useful in the local control of metastatic tumors, and in the survival of patients with tumor factors, such as small size or the absence of extracranial tumor activity, and host factors, such as young age or good performance status.

Although induction chemotherapy can reduce distant metastases in locally advanced head and neck squamous cell carcinoma (HNSCC), overall survival (OS) improvement because of induction chemotherapy has not been confirmed.We reviewed medical records of 224 patients diagnosed with locally advanced HNSCC who were treated with induction chemotherapy followed by concurrent chemoradiotherapy (CRT; induction chemotherapy/CRT; N = 144) and CRT alone (N = 80) from 2005 to 2013. We analyzed OS and progression-free survival (PFS).The 3-year OS rate was significantly higher in the induction chemotherapy/CRT group compared to the CRT group (74.0% vs 62.7%; p = .045). The 3-year PFS rate was 64.6% in the induction chemotherapy/CRT group and 54.1% in the CRT group (p = .060). Subgroup analysis showed patients with high N classification (N2 or N3) oropharyngeal cancer had greater benefits when treated with induction chemotherapy/CRT.Induction chemotherapy plus CRT improved OS, compared to CRT alone in locally advanced HNSCC, especially with high N classification.

PURPOSE The purpose of this study was to evaluate whether an exogenous epidermal growth factor (EGF) could induce anti-tumor and radiosensitizing effects in vivo. MATERIALS AND METHODS BALB/c-nu mice that were inoculated with A431 (human squamous cell carcinoma) cells in the right hind legs were divided into five groups: I (no treatment), II (EGF for 6 days), III (EGF for 20 days), IV (radiotherapy [RT]), and V (RT plus concomitant EGF). EGF was administered intraperitoneally (5 mg/kg) once a day and the RT dose was 30 Gy in six fractions. Hematoxylin and eosin (H&E) stained sections of tumor, liver, lung, and kidney tissues were investigated. Additionally, tumors were subjected to immunohistochemistry staining with caspase-3. RESULTS EGF for 6 days decreased tumor volume, but it approached the level of the control group at the end of follow-up (p=0.550). The duration of tumor shrinkage was prolonged in group V while the slope of tumor re-growth phase was steeper in group IV (p=0.034). EGF for 20 days decreased tumor volume until the end of the observation period (p < 0.001). Immunohistochemistry revealed that mice in group V showed stronger intensity than those in group IV. There were no abnormal histological findings upon H&E staining of the normal organs. CONCLUSION EGF-induced anti-tumor effect was ascertained in the xenograft mouse models with A431 cells. Concomitant use of EGF has the potential role as a radiosensitizer in the design of fractionated irradiation.

The objective of this study was to evaluate the psychometric properties of the Smart Management Strategy for Health Assessment Tool (SAT), which we developed to enable cancer patients to assess their self-management (SM) strategies of health by themselves.The development of the questionnaire included four phases: item generation, construction, pilot testing, and field testing. To assess the instrument's sensitivity and validity, we recruited 300 cancer patients from three Korean hospitals who were 18 or more years old and accustomed to using the Internet or email. Using the appropriate and priority criteria for pilot and field testing, we tightened the content and constructed the first version of the SAT.We developed the core strategies with 28 items, preparation strategies with 30 items, and implementation strategies with 33 items. Factor analysis of data from 300 patients resulted in core strategies with four factors, preparation strategies with five factors, and implementation strategies with six factors. All the SAT subscales demonstrated a high reliability with good internal consistency. The total scores of the three SAT sets differentiated participant groups well according to their stage of goal implementation and proportions of action of the 10 Rules for Highly Effective Health Behavior. Each factor of the three SAT sets correlated positively with the scores for additional assessment tool.The SAT is a three-set, 16-factor, 91-item tool that assesses the SM strategies of health that patients use to overcome a crisis. Patients can use the SAT to assess their SM strategies of health and obtain feedback from clinicians in the practice setting.

Purpose This study was designed to evaluate the efficacy and safety of topically applied recombinant human epidermal growth factor (rhEGF) for the prevention of radiation-induced dermatitis in cancer patients. Materials and methods From December 2010 to April 2012, a total of 1,172 cancer patients who received radiotherapy (RT) of more than 50 Gy were prospectively enrolled and treated with EGF-based cream. An acute skin reaction classified according to the Radiation Therapy Oncology Group 6-point rating scale was the primary end point and we also assessed the occurrence of edema, dry skin, or pruritus. Results The percentage of radiation dermatitis with maximum grade 0 and grade 1 was 19% and 58% at the time of 50 Gy, and it became 29% and 47% after completion of planned RT. This increment was observed only in breast cancer patients (from 18%/62% to 32%/49%). Adverse events related to the EGF-based cream developed in 49 patients (4%) with mild erythema the most common. Skin toxicity grade >2 was observed in 5% of the patients. Edema, dry skin, and pruritus grade ≥3 developed in 9%, 9%, and 1% of the patients, respectively. Conclusion Prophylactic use of an EGF-based cream is effective in preventing radiation dermatitis with tolerable toxicity. Further studies comparing EGF cream with other topical agents may be necessary.

Objective: To investigate predictors affecting the development of hypothyroidism after radiotherapy for head and neck cancer, focusing on radiation dose-volumetric parameters, and to determine the appropriate radiation dose-volumetric threshold of radiation-induced hypothyroidism. Methods: A total of 114 patients with head and neck cancer whose radiotherapy fields included the thyroid gland were analysed. The purpose of the radiotherapy was either definitive (n ¼ 81) or post-operative (n ¼ 33). Thyroid function was monitored before starting radiotherapy and after completion of radiotherapy at 1 month, 6 months, 1 year and 2 years. A diagnosis of hypothyroidism was based on a thyroid stimulating hormone value greater than the maximum value of laboratory range, regardless of symptoms. In all patients, dose volumetric parameters were analysed. Results: Median follow-up duration was 25 months (range; 6‐38). Forty-six percent of the patients were diagnosed as hypothyroidism after a median time of 8 months (range; 1‐24). There were no significant differences in the distribution of age, gender, surgery, radiotherapy technique and chemotherapy between the euthyroid group and the hypothyroid group. In univariate analysis, the mean dose and V35‐V50 results were significantly associated with hypothyroidism. The V45 is the only variable that independently contributes to the prediction of hypothyroidism in multivariate analysis and V45 of 50% was a threshold value. If V45 was ,50%, the cumulative incidence of hypothyroidism at 1 year was 22.8%, whereas the incidence was 56.1% if V45 was 50% (P ¼ 0.034). Conclusions: The V45 may predict risk of developing hypothyroidism after radiotherapy for head and neck cancer, and a V45 of 50% can be a useful dose-volumetric threshold of radiation-induced hypothyroidism.

The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P

SummaryAlthough the overall risk of venous thromboembolism (VTE) is high in patients with non-small cell lung cancer (NSCLC), risk identification is limited. The goal of this study was to estimate the incidence, risk factors and prognostic implications of VTE, and to evaluate a genetic link between oncogenes and the risk of VTE in Asian patients with NSCLC. A total of 1,998 consecutive patients with NSCLC were enrolled and analysed retrospectively. Since the effects of therapeutics on VTE development were modified by stage, stratified analyses were performed. When comparing overall survival in terms of VTE development, a propensity score-matching method was adopted to minimise potential confounding. The six-month and two-year cumulative incidences of VTE were 4.2% and 6.4%, respectively. The risk of VTE increased 2.45-fold with each advancing stage in NSCLC (p

Author Summary Lessons Learned Addition of cetuximab may affect tolerability and, in turn, affect eventual outcomes. The incidence of prior human papillomavirus infection has emerged as an important variable that can confound trials enrolling patients with oropharyngeal cancer. Background. We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma. Methods. Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy. Results. Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively. Conclusion. Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.

Authors designed a customized small bowel displacement system (SBDS) to displace the small bowel out of the pelvic radiation fields and to minimize treatment related bowel morbidity.From August 1995 to May 1996, 55 consecutive patients who received pelvic radiation therapy with the SBDS were included in this study. The SBDS consists of a customized Styrofoam compression device that can displace the small bowel out of the radiation fields and an individualized immobilization abdominal board for easy daily setup of the patient in prone position. After opacifying the small bowel with barium, the patients were laid prone and posterior-anterior (PA) and lateral (LAT) simulation films were taken with and without the SBDS. The volume of the small bowel included in the radiation fields with and without the SBDS were compared.Using the SBDS, the mean small bowel volume was reduced by 59% on PA and 51% on LAT films (p = 0.0001). In six patients (6 of 55, 11%), it was possible that no small bowel was included within the treatment fields. The mean upward displacement of the most caudal small bowel was 4.8 cm using the SBDS. Patients treated with the SBDS manifested a significantly lower incidence of diarrhea requiring medication (8 of 55, 15%) vs. those without the SBDS (24 of 39, 62%) (p0.05).The SBDS is a novel method that can be used to displace the small bowel away from the treatment portal effectively and to reduce the radiation therapy morbidity. Compliance with setup is excellent.

Patients with cervical cancer who have positive surgical resection margins after radical hysterectomy are at increased risk for local recurrence. The results of postoperative pelvic radiotherapy for cervix cancer with microscopically positive surgical resection margins were analyzed to evaluate the role of radiotherapy. Between 1979 and 1992, 60 patients with cervix carcinoma were treated with postoperative radiotherapy after radical hysterectomy and pelvic lymphadenectomy because of microscopic positive vaginal (48 patients), or parametrial (12 patients) resection margins. Patients were treated with external beam radiation therapy (EBRT) alone (12 patients), or EBRT plus vaginal ovoid irradiation (VOI) (48 patients). The median follow-up period was 55 months. The 5-year actuarial disease-free and overall survival rates for all patients were 75% and 84%, respectively. The overall recurrence rate was 23% (14/60). Among the 48 patients with positive vaginal resection margins, 4 had pelvic recurrence (8%), and 7 had distant metastasis (15%); the recurrence rate was 21% (9/43) in those treated with EBRT and VOI, and 40% (2/5) in the EBRT-only treated group. In the 12 patients with positive parametrial margins, 3 patients (25%) had distant metastases. The most significant prognostic factor was lymph node metastasis. Complications resulting from radiotherapy occurred at a rate of 32% (19/60), and grade III complications occurred in 3 patients (5%). Postoperative radiotherapy can produce excellent control rates in patients with microscopically positive resection margins. In patients with positive vaginal margins, whole pelvic EBRT and VOI is recommended.

PURPOSE WE EVALUATED THE EFFECTIVENESS AND SAFETY OF IPSILATERAL RADIOTHERAPY FOR THE PATIENT WITH WELL LATERALIZED TONSIL CANCER: not cross midline and

Purpose The purpose of this study was to assess the clinical outcomes of hypofractionated radiotherapy (HFRT) with three-dimensional conformal technique for medically inoperable patients with early stage non-small-cell lung cancer (NSCLC) and to evaluate prognostic factors. Materials and methods We performed a retrospective review of 26 patients who underwent HFRT for early stage NSCLC between September 2005 and August 2011. Only clinical stage T1-3N0 was included. The median RT dose was 70 Gy (range, 60 to 72 Gy) and the median biologically equivalent dose (BED) was 94.5 Gy (range, 78.0 to 100.8 Gy). In 84.6% of patients, 4 Gy per fraction was used. Neoadjuvant chemotherapy with paclitaxel and cisplatin was given to 2 of 26 patients. Results The median follow-up time for surviving patients was 21 months (range, 13 to 49 months). The overall response rate was 53.9%, and the initial local control rate was 100%. The median survival duration was 27.8 months. Rates of 2-year overall survival, progression-free survival (PFS), local control (LC), and locoregional-free survival (LRFS) were 54.3%, 61.1%, 74.6%, and 61.9%, respectively. Multivariate analysis showed that BED (>90 vs. ≤90 Gy) was an independent prognostic factor influencing PFS, LC, and LRFS. Severe toxicities over grade 3 were not observed. Conclusion Radical HFRT can yield satisfactory disease control with acceptable rates of toxicities in medically inoperable patients with early stage NSCLC. HFRT is a viable alternative for clinics and patients ineligible for stereotactic ablative radiotherapy. BED over 90 Gy and 4 Gy per fraction might be appropriate for HFRT.