Concurrent Chemoradiation with Low-Dose Weekly Cisplatin in Locally Advanced Stage IV Head and Neck Squamous Cell Carcinoma.

PURPOSE: Concurrent chemoradiation (CRT) with 3-weekly doses of cisplatin is a standard treatment for loco-regionally advanced head and neck squamous cell carcinoma (HNSCC). However, treatment with 3-weekly doses of cisplatin is often associated with several adverse events. Therefore, we conducted this retrospective analysis to determine the efficacy and tolerance of CRT with a low weekly dose of cisplatin in stage IV HNSCC patients. MATERIALS AND METHODS: Medical records of patients who were diagnosed with stage IV HNSCC and received concurrent CRT were analyzed. All patients were treated weekly with cisplatin at 20-30 mg/m(2) until radiotherapy was completed. RESULTS: A total of 35 patients were reviewed. Median follow up was 10.7 months (range, 1.7 to 90.5 months), the median radiation dose was 7,040 cGy, and the median dose of cisplatin received was 157 mg/m(2). Eleven patients received docetaxel combination chemotherapy. Overall, 25 patients (71.4%) achieved complete response (CR), eight (22.9%) showed partial response. The median overall survival was 42.7 months, the 3-year survival rate was 51.2% and the 3 year disease-free survival rate was 72.8%. Overall survival was improved in patients who achieved CR relative to others (59.7 months vs. 13.4 months; p=0.008). There were significant differences in survival between patients who received docetaxel combination and cisplatin alone (51.8 months vs. 7.9 months; p=0.009). Grade 3-4 adverse events included stomatitis (82.9%), dermatitis (22.9%), infection (11.4%), dysphagia (8.6%), and neutropenia (5.7%). CONCLUSION: CRT with low dose weekly cisplatin is likely effective and tolerable, even in patients with locally advanced-stage IV HNSCC.

A prospective randomized trial comparing hypofractionation with conventional fractionation radiotherapy for T1-2 glottic squamous cell carcinomas: results of a Korean Radiation Oncology Group (KROG-0201) study.

BACKGROUND AND PURPOSE: To prospectively investigate the effect of radiotherapy fraction size on clinical outcomes in early glottic carcinoma METHODS AND MATERIALS: Patients with T1-2 glottic carcinoma were eligible for the protocol. Although 282 patients were required, the study was closed prematurely due to poor accrual with only 156 patients. Of these, 82 patients were allocated to conventional fractionation (CONV) arm (66 Gy/33 fractions for T1 and 70 Gy/35 fractions for T2), with 74 patients to hypofractionation (HYPO) arm (63 Gy/28 fractions for T1 and 67.5 Gy/30 fractions for T2). The primary objective was local progression-free survival (LPFS). RESULTS: With a median follow-up of 67 months (range, 2-122 months), the 5-year LPFS was 77.8% for CONV arm and 88.5% for HYPO arm (HR 1.55, p=0.213). No significant difference was observed in the toxicity profile between the two arms. In a subgroup exploratory analysis for T1a disease, the 5-year LPFS trended positively in HYPO arm (76.7% vs. 93.0%, HR 3.65, p=0.056). CONCLUSIONS: Given that HYPO is at least not inferior to CONV with a similar toxicity profile, the hypofractionation scheme used in this study can be offered to patients with T1-2 glottic carcinoma with potential advantages in terms of local control and a shortened overall treatment time.

Estimation of optimal margin for intrafraction movements during frameless brain radiosurgery.

PURPOSE: To examine the dosimetric effect of intrafraction movements occurred during image-guided frameless brain radiosurgery and to derive the optimal margin recipe to compensate the movement. METHODS: The patients' movements during image-guided radiosurgeries were measured using skull-tracking method incorporated in the CyberKnife system. The dosimetric changes with the movements were computed using the six different dynamic-arc treatment plans based on the dose-grid analysis method. The authors extensively searched the proper relationship between the dose variations and the intrafraction geometric errors. The optimal margin for intrafraction movement was estimated via statistical analysis of the dosimetric changes with 262 actual patients' data. RESULTS: The overall geometric effect of intrafraction movements was approximated as 1.0 r+0.2σ, where r and σ are the average and standard deviation of the movements, respectively. The authors computed the required margins to compensate the movements with various confidence levels and with various estimated times for completing the treatments. The computed optimal margins were calculated as 2.1, 3.2, and 4.2 mm at 90% confidence level when the authors assumed the estimated treatment times of 10, 20, and 30 min, respectively. CONCLUSIONS: The authors provide a quantitative relationship for dosimetric change with the intrafraction movement and derived appropriate margin recipes to ensure the prescribed dose delivery to targeted area for frameless brain radiosurgery.

Compensation method for respiratory motion in proton treatment planning for mobile liver cancer.

We evaluated the dosimetric effect of a respiration motion, and sought an effective planning strategy to compensate the motion using four-dimensional computed tomography (4D CT) dataset of seven selected liver patients. For each patient, we constructed four different proton plans based on: (1) average (AVG) CT, (2) maximum-intensity projection (MIP) CT, (3) AVG CT with density override of tumor volume (OVR), and (4) AVG CT with field-specific proton margin which was determined by the range difference between AVG and MIP plans (mAVG). The overall effectiveness of each planning strategy was evaluated by calculating the cumulative dose distribution over an entire breathing cycle. We observed clear differences between AVG and MIP CT-based plans, with significant underdosages at expiratory and inspiratory phases, respectively. Only the mAVG planning strategy was fully successful as the field-specific proton margin applied in the planning strategy complemented both the limitations of AVG and MIP CT-based strategies. These results demonstrated that respiration motion induced significant changes in dose distribution of 3D proton plans for mobile liver cancer and the changes can be effectively compensated by applying field-specific proton margin to each proton field.

Effect of early chemoradiotherapy in patients with limited stage small cell lung cancer.

PURPOSE: We evaluated the effect of early chemoradiotherapy on the treatment of patients with limited stage small cell lung cancer (LS-SCLC). MATERIALS AND METHODS: Between January 2006 and December 2011, thirty-one patients with histologically proven LS-SCLC who were treated with two cycles of chemotherapy followed by concurrent chemoradiotherapy and consolidation chemotherapy were retrospectively analyzed. The chemotherapy regimen was composed of etoposide and cisplatin. Thoracic radiotherapy consisted of 50 to 60 Gy (median, 54 Gy) given in 5 to 6.5 weeks. RESULTS: The follow-up period ranged from 5 to 53 months (median, 22 months). After chemoradiotherapy, 35.5% of the patients (11 patients) showed complete response, 61.3% (19 patients) showed partial response, 3.2% (one patient) showed progressive disease, resulting in an overall response rate of 96.8% (30 patients). The 1-, 2-, and 3-year overall survival (OS) rates were 66.5%, 41.0%, and 28.1%, respectively, with a median OS of 21.3 months. The 1-, 2-, and 3-year progression free survival (PFS) rates were 49.8%, 22.8%, and 13.7%, respectively, with median PFS of 12 months. The patterns of failure were: locoregional recurrences in 29.0% (nine patients), distant metastasis in 9.7% (three patients), and both locoregional and distant metastasis in 9.7% (three patients). Grade 3 or 4 toxicities of leukopenia, anemia, and thrombocytopenia were observed in 32.2%, 29.0%, and 25.8%, respectively. Grade 3 radiation esophagitis and radiation pneumonitis were shown in 12.9% and 6.4%, respectively. CONCLUSION: We conclude that early chemoradiotherapy for LS-SCLC provides feasible and acceptable local control and safety.

Concurrent chemoradiotherapy for elderly patients with stage III non-small cell lung cancer.

PURPOSE: Combined chemoradiotherapy is standard management for locally advanced non-small cell lung cancer (LA-NSCLC), but standard treatment for elderly patients with LA-NSCLC has not been confirmed yet. We evaluated the feasibility and efficacy of concurrent chemoradiotherapy (CCRT) for elderly patients with LA-NSCLC. MATERIALS AND METHODS: Among patients older than 65 years with LA-NSCLC, 36 patients, who underwent CCRT were retrospectively analyzed. Chemotherapy was administered 3-5 times with 4 weeks interval during radiotherapy. Thoracic radiotherapy was delivered to the primary mass and regional lymph nodes. Total dose of 54-59.4 Gy (median, 59.4 Gy) in daily 1.8 Gy fractions and 5 fractions per week. RESULTS: Regarding the response to treatment, complete response, partial response, and no response were shown in 16.7%, 66.7%, and 13.9%, respectively. The 1- and 2-year overall survival (OS) rates were 58.2% and 31.2%, respectively, and the median survival was 15 months. The 1- and 2-year progression-free survivals (PFS) were 41.2% and 19.5%, respectively, and the median PFS was 10 months. Regarding to the toxicity developed after CCRT, pneumonitis and esophagitis with grade 3 or higher were observed in 13.9% (5 patients) and 11.1% (4 patients), respectively. Treatment-related death was not observed. CONCLUSION: The treatment-related toxicity as esophagitis and pneumonitis were noticeably lower when was compared with the previously reported results, and the survival rate was higher than radiotherapy alone. The results indicate that CCRT is an effective in terms of survival and treatment related toxicity for elderly patients over 65 years old with LA-NSCLC.

Discordance in perceived needs between patients and physicians in oncology practice: a nationwide survey in Korea.

PURPOSE: Identification of supportive care needs in patients with cancer is essential for planning appropriate interventions. We aimed to determine patient-physician concordance in perceived supportive care needs in cancer care and to explore the predictors and potential consequences of patient-physician concordance. PATIENTS AND METHODS: A national, multicenter, cross-sectional survey of patient-physician dyads was performed, and 97 oncologists (participation rate, 86.5%) and 495 patients (participation rate, 87.4%) were included. A short form of the Comprehensive Needs Assessment Tool for Cancer Patients was independently administered to patients and their oncologists. Concordance and agreement rates between physicians and patients were calculated. Mixed logistic regression was used to identify predictors of concordance and to explore the association of concordance with patient satisfaction and trust in physicians. RESULTS: Physicians systematically underestimated patient needs and patient-physician concordance was generally poor, with weighted κ statistics ranging from 0.04 to 0.15 for individual items and Spearman's ρ coefficients ranging from 0.11 to 0.21 for questionnaire domains. Length of experience as oncologist was the only significant predictor of concordance (adjusted odds ratio for overall concordance [aOR] = 2.09; 95% CI, 1.02 to 4.31). Concordance was not significantly associated with overall patient satisfaction (aOR = 1.24; 95% CI, 0.74 to 2.07) or trust in physician (aOR = 1.17; 95% CI, 0.76 to 1.81). CONCLUSION: Our findings revealed significant underestimation of patient needs and poor concordance between patients and physicians in assessing perceived needs of supportive care. The clinical implications of this discordance warrant further investigation.

Quantitative analysis of myosin heavy chain expression change in laryngeal muscle after irradiation in rats.

PURPOSE: Radiotherapy for head and neck cancer does not impair the voice quality as much as laser treatment or surgery, but it can induce muscle wasting and fibrosis and symptoms of dry mouth. We investigated the effect of irradiation on the myosin heavy chain (MyHC) expression in laryngeal muscles. MATERIALS AND METHODS: Rats were irradiated with one dose of 10, 15, 20, 25, 30, or 35 Gy and other rats were irradiated with 20 Gy. The thyroarytenoid (TA), posterior cricoarytenoid (PCA), and cricothyroid (CT) muscles were subjected to reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Two weeks after irradiation with 10, 15, or 20 Gy, all the MyHC type expressions had decreased in a dose-dependent manner in the TA, PCA, and CT muscles, and especially the expression of MyHC IIa decreased much more than the expressions of the other MyHC isoforms in all muscles. In the 20 Gy-irradiated rats, almost all the MyHC isoform expressions declined over 12 weeks in the TA, PCA, and CT muscles, except for the MyHC I expression in the PCA and CT muscle. The MyHC IIa expression was markedly decreased in all the muscles. CONCLUSION: The laryngeal muscles responded differently to radiation, but they showed a time-dependent and long-lasting decrease in the expressions of all the MyHC isoforms in the TA, PCA, and CT muscles. In particular, the expression of the MyHC IIa isoform in all the muscles may be more sensitive to irradiation than the expressions of the other MyHC isoforms.

Therapeutic effects of recombinant human epidermal growth factor (rhEGF) in a murine model of concurrent chemo- and radiotherapy-induced oral mucositis.

Concurrent chemotherapy with radiotherapy (CCRT) has been applied for the treatment of advanced stage of head and neck cancer patients. However CCRT is associated with several complications including mucositis, dermatitis, stomatitis, etc. This study was conducted to evaluate the therapeutic effect of systemically administrated recombinant human epidermal growth factor (rhEGF) in CCRT-induced oral mucositis in a mouse model. Oral mucositis was induced in male BALB/c mice through combination treatment with cisplatin (11 mg/kg, i.p.) and irradiation (17 Gy) of the head and neck area. rhEGF (1.0 mg/kg/day for consecutive 3 days) was administered systemically, and the therapeutic effect was determined by histological evaluation of the oral mucosa. To elucidate optimal dose of rhEGF on CCRT-induced mucositis, various concentrations (0.04-3 mg/kg) of rhEGF were injected for 3 days. Systemic rhEGF administration accelerated the recovery of body weight. Histologically, rhEGF-treated mice showed significantly increased epithelial cell layer thickness, basal cell number, and expression of Ki-67 compared to control mice. Most effective dose was 1 mg/kg among other doses tested. Systemic administration of 1 mg/kg of rhEGF reduces the severity of oral mucositis induced by CCRT in a mouse model, suggesting that rhEGF can be used for treating CCRT-induced mucositis during the cancer treatment.

Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis.

BACKGROUND: The objectives of this retrospective study was to evaluate the efficacy of stereotactic body radiation therapy (SBRT) for small non-resectable hepatocellular carcinoma (HCC) and SBRT combined with transarterial chemoembolization (TACE) for advanced HCC with portal vein tumor thrombosis (PVTT). METHODS: Thirty one patients with HCC who were treated with SBRT were used for the study. We studied 32 HCC lesions, where 23 lesions (22 patients) were treated targeting small non-resectable primary HCC, and 9 lesions (9 patients) targeting PVTT using the Cyberknife. All the 9 patients targeting PVTT received TACE for the advanced HCC. Tumor volume was 3.6-57.3 cc (median, 25.2 cc) and SBRT dose was 30-39 Gy (median, 36 Gy) in 3 fractions for consecutive days for 70-85% of the planned target volume. RESULTS: The median follow up was 10.5 months. The overall response rate was 71.9% [small HCC: 82.6% (19/23), advanced HCC with PVTT: 44.4% (4/9)], with the complete and partial response rates of 31.3% [small HCC: 26.1% (6/23), advanced HCC with PVTT: 11.1% (1/9)], and 50.0% [small HCC: 56.5% (13/23), advanced HCC with PVTT: 33.3% (3/9)], respectively. The median survival period of small HCC and advanced HCC with PVTT patients was 12 months and 8 months, respectively. No patient experienced Grade 4 toxicity. CONCLUSION: SBRT for small HCC and SBRT combined with TACE for advanced HCC with PVTT showed feasible treatment modalities with minimal side effects in selected patients with primary HCC.

Bisacurone inhibits adhesion of inflammatory monocytes or cancer cells to endothelial cells through down-regulation of VCAM-1 expression.

Bisacurone, one of the active compounds of the traditionally used indigenous herb Curcuma longa Linne (Zingiberaceae), has anti-oxidant, anti-inflammatory, and anti-metastatic activities. We studied how the level of vascular cell adhesion molecule-1 (VCAM-1), one of the key molecules in the development of atherosclerosis as well as carcinogenesis and metastasis, might be affected by bisacurone in tumor necrosis factor-alpha (TNF-alpha)-activated human umbilical vein endothelial cells (HUVECs). Bisacurone dose-dependently inhibited TNF-alpha-mediated expression of VCAM-1. It showed significant suppressive effect on ROS generation in response to TNF-alpha stimulation and it blocked nuclear factor-kappa B (NF-kappaB) p65 translocation into the nucleus and phosphorylation of inhibitory factor kappaBalpha (IkappaBalpha). It also inhibited phosphorylation of Akt and PKC, which are upstream in the regulation of VCAM-1 by TNF-alpha. Furthermore, bisacurone decreased U937 monocyte and human oral cancer cell (Hep-2, QLL-I, SCC-15) adhesion to HUVECs stimulated by TNF-alpha, suggesting that it may inhibit the binding of these cells by regulating the expression of critical adhesion molecules by TNF-alpha. Thus, bisacurone may be beneficial in the treatment of inflammatory diseases, such as atherosclerosis, where inflammatory monocytes are involved in their pathology, and, moreover, in the development of tumors.

Clinical significance of loss of heterozygosity for M6P/IGF2R in patients with primary hepatocellular carcinoma.

AIM: To investigate the relationship between loss of heterozygosity (LOH) for mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) and the outcomes for primary HCC patients treated with partial hepatectomy. METHODS: The LOH for M6P/IGF2R in primary HCC patients was assessed using six different gene-specific nucleotide polymorphisms. The patients studied were enrolled to undergo partial hepatectomy. RESULTS: M6P/IGF2R was found to be polymorphic in 73.3% (22/30) of the patients, and of these patients, 50.0% (11/22) had tumors showing LOH in M6P/IGF2R. Loss of heterozygosity in M6P/IGF2R was associated with significant reductions in the two year overall survival rate (24.9% vs 65.5%; P=0.04) and the disease-free survival rate (17.8% vs 59.3%; P=0.03). CONCLUSION: These results show M6P/IGF2R LOH predicts poor clinical outcomes in surgically resected primary HCC patients.

Fractionated stereotactic radiotherapy in patients with primary hepatocellular carcinoma.

OBJECTIVE: The purpose of our study was to evaluate the feasibility and treatment outcomes of fractionated stereotactic radiotherapy (SRT) for primary hepatocellular carcinoma (HCC). METHODS: We enrolled 20 patients who had been histologically diagnosed as HCC patients and treated by fractionated SRT. Tumor size was 2-6.5 cm (average: 3.8 cm). We prescribed 50 Gy in 5 or 10 fractions at the 85-90% isodose line of the planning target volume for 2 weeks. The follow-up period was 3-55 months (median: 23 months). RESULTS: The overall response rate was 80%, with 4 patients showing complete response (20%), 14 patients showing partial response (60%) and 4 patients showing stable disease (20%). The 1-year and 2-year survival rates were 70.0 and 43.1%, respectively (median: 20 months). The 1-year and 2-year disease-free survival rates were 65.0 and 32.5%, respectively (median: 19 months). The fractionated SRT was well tolerated, because grade 3 or grade 4 toxicity was not observed. CONCLUSION: These results suggest that fractionated SRT is a relatively safe and effective method for treating small primary HCC. Thus, fractionated SRT may be suggested as a local treatment of choice for small HCC when the patients are inoperable or when the patients refuse operation.

Impact of intensity-modulated radiation therapy as a boost treatment on the lung-dose distributions for non-small-cell lung cancer.

PURPOSE: To investigate the feasibility of intensity-modulated radiotherapy (IMRT) as a method of boost radiotherapy after the initial irradiation by the conventional anterior/posterior opposed beams for centrally located non-small-cell lung cancer through the evaluation of dose distributions according to the various boost methods. METHODS AND MATERIALS: Seven patients with T3 or T4 lung cancer and mediastinal node enlargement who previously received radiotherapy were studied. All patients underwent virtual simulation retrospectively with the previous treatment planning computed tomograms. Initial radiotherapy plans were designed to deliver 40 Gy to the primary tumor and involved nodal regions with the conventional anterior/posterior opposed beams. Two radiation dose levels, 24 and 30 Gy, were used for the boost radiotherapy plans, and four different boost methods (a three-dimensional conformal radiotherapy [3DCRT], five-, seven-, and nine-beam IMRT) were applied to each dose level. The goals of the boost plans were to deliver the prescribed radiation dose to 95% of the planning target volume (PTV) and minimize the volumes of the normal lungs and spinal cord irradiated above their tolerance doses. Dose distributions in the PTVs and lungs, according to the four types of boost plans, were compared in the boost and sum plans, respectively. RESULTS: The percentage of lung volumes irradiated >20 Gy (V20) was reduced significantly in the IMRT boost plans compared with the 3DCRT boost plans at the 24- and 30-Gy dose levels (p = 0.007 and 0.0315 respectively). Mean lung doses according to the boost methods were not different in the 24- and 30-Gy boost plans. The conformity indexes (CI) of the IMRT boost plans were lower than those of the 3DCRT plans in the 24- and 30-Gy plans (p = 0.001 in both). For the sum plans, there was no difference of the dose distributions in the PTVs and lungs according to the boost methods. CONCLUSIONS: In the boost plans the V20s and CIs were reduced significantly by the IMRT plans, but in the sum plans the effects of IMRT on the dose distributions in the tumor and lungs, like CI and V20, were offset. Therefore, to keep the beneficial effect of IMRT in radiotherapy for lung cancer, it would be better to use IMRT as a whole treatment plan rather than as a boost treatment.