Chia-Hsuan Lai

Predictive factors of radiation-induced skin toxicity in breast cancer patients

BackgroundTo assess the factors affecting the incidence of radiation-induced dermatitis in breast cancer patients treated with adjuvant 3 D conformal radiotherapy by the analysis of dosimetry and topical treatments.MethodsBetween September 2002 and July 2009, 158 breast cancer patients were treated with adjuvant 3 D conformal radiotherapy after undergoing surgery. Before November 2006, 90 patients were subjected to therapeutic skin care group and topical corticosteroid therapy was used for acute radiation dermatitis. Thereafter, 68 patients received prophylactic topical therapy from the beginning of radiotherapy. The two groups did not differ significantly in respect of clinical and treatment factors. Furthermore, the possible mechanisms responsible for the effects of topical treatment on radiation-induced dermatitis were investigated in vivo.ResultsThe incidence of radiation-induced moist desquamation was 23% across 158 patients. Higher volume receiving 107% of prescribed dose within PTV (PTV-V107%; >28.6%) and volume receiving 110% of prescribed dose within treated volume (TV-V110%; > 5.13%), and no prophylactic topical therapy for irradiated skin, were associated with higher incidence of acute radiation dermatitis. The protective effect of prophylactic topical treatment was more pronounced in patients with TV-V110% > 5.13%. Furthermore, using irradiated mice, we demonstrated that topical steroid cream significantly attenuated irradiation-induced inflammation, causing a decrease in expression of inflammatory cytokines and TGF-beta 1.ConclusionTV-V110% > 5.13% may be an important predictor for radiation induced dermatitis. Prophylactic topical treatment for irradiated skin can significantly improve the tolerance of skin to adjuvant radiotherapy, especially for patients with higher TV-V110%.

Comparison between conventional and intensity-modulated post-operative radiotherapy for stage III and IV oral cavity cancer in terms of treatment results and toxicity

The aim of this study was to assess the treatment results and toxicity profiles of post-operative conventional radiotherapy (Conv-RT) and intensity-modulated radiotherapy (IMRT) for stage III and IV oral cavity cancer. During the period from April 2002 to December 2005, a total of 49 patients with stage III and IV squamous cell carcinoma of the oral cavity were treated with radical surgery followed by post-operative RT. Twenty-seven patients received Conv-RT while 22 received IMRT. Only three patients received adjuvant chemotherapy. With a median follow-up time of 3.3 years, the 3-year overall survival and disease-free survival rates for patients who received Conv-RT vs IMRT were comparable. There was no significant difference in acute toxicity between the two different RT techniques. However, in terms of late toxicity, patients receiving IMRT had significantly less moderate to severe xerostomia and dysphagia than those receiving Conv-RT (36% vs 82%, p=0.01 for xerostomia and 21% vs 59%, p=0.02 for dysphagia). Post-operative Conv-RT and IMRT are equally effective in terms of tumor control for locally advanced oral cavity cancer. Patients receiving IMRT had comparable acute and significant less late toxicity than those receiving Conv-RT.

Scintigraphic assessment of salivary function after intensity-modulated radiotherapy for head and neck cancer: Correlations with parotid dose and quality of life

OBJECTIVE We investigated salivary function using quantitative scintigraphy and sought to identify functional correlations between parotid dose and quality of life (QoL) for head and neck cancer (HNC) patients receiving intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS Between August, 2007 and June, 2008, 31 patients treated IMRT for HNC were enrolled in this prospective study. Salivary excretion function (SEF) was previously measured by salivary scintigraphy at annual intervals for 2 years after IMRT. A dose-volume histogram of each parotid gland was calculated, and the normal tissue complication probability (NTCP) was used to determine the tolerance dose. QoL was longitudinally assessed by the EORTC QLQ-C30 and H&N35 questionnaires prior to RT, and at one, three, 12 and 24 months after RT. RESULTS A significant correlation was found between the reduction of SEF and the mean parotid dose measured at 1 year (correlation coefficient, R(2)=0.651) and 2 years (R(2)=0.310) after IMRT (p<0.001). The TD(50) of the parotid gland at 1 year after IMRT is 43.6 Gy, comparable to results from western countries. We further found that contralateral parotid and submandibular gland function preservation was correlated with reduced sticky saliva and a better QoL compared to the functional preservation of both parotid glands, as determined by the EORTC QLQ-H&N35 questionnaire. CONCLUSION A significant correlation was found between the reduction of SEF and the mean parotid dose. Preservation of contralateral parotid and submandibular gland function predicts a better QoL compared to preservation of the function of both parotid glands.

Role of Interleukin-6 in the Radiation Response of Liver Tumors

PURPOSE To investigate the role of interleukin (IL)-6 in biological sequelae and tumor regrowth after irradiation for hepatic malignancy, which are critical for the clinical radiation response of liver tumors. METHODS AND MATERIALS The Hepa 1-6 murine hepatocellular cancer cell line was used to examine the radiation response by clonogenic assays and tumor growth delay in vivo. After irradiation in a single dose of 6 Gy in vitro or 15 Gy in vivo, biological changes including cell death and tumor regrowth were examined by experimental manipulation of IL-6 signaling. The effects of blocking IL-6 were assessed by cells preincubated in the presence of IL-6-neutralizing antibody for 24 hours or stably transfected with IL-6-silencing vectors. The correlations among tumor responses, IL-6 levels, and myeloid-derived suppressor cells (MDSC) recruitment were examined using animal experiments. RESULTS Interleukin-6 expression was positively linked to irradiation and radiation resistance, as demonstrated by in vitro and in vivo experiments. Interleukin-6-silencing vectors induced more tumor inhibition and DNA damage after irradiation. When subjects were irradiated with a sublethal dose, the regrowth of irradiated tumors significantly correlated with IL-6 levels and MDSC recruitment in vivo. Furthermore, blocking of IL-6 could overcome irradiation-induced MDSC recruitment and tumor regrowth after treatment. CONCLUSION These data demonstrate that IL-6 is important in determining the radiation response of liver tumor cells. Irradiation-induced IL-6 and the subsequent recruitment of MDSC could be responsible for tumor regrowth. Therefore, treatment with concurrent IL-6 inhibition could be a potential therapeutic strategy for increasing the radiation response of tumors.

Inflammation-induced myeloid-derived suppressor cells associated with squamous cell carcinoma of the head and neck.

The purpose of this study was to present our assessment of the significance of myeloid‐derived suppressor cells (MDSCs) in head and neck squamous cell carcinoma (HNSCC).

Identification of High-Risk Subgroups of Patients With Oral Cavity Cancer in Need of Postoperative Adjuvant Radiotherapy or Chemo-Radiotherapy.

AbstractPatients with oral cavity squamous cell carcinoma (OSCC) undergoing surgery are recommended to receive adjuvant radiation therapy with or without chemotherapy if there are unfavorable prognostic factors. A positive resection margin (PRM) and extra-capsular extension (ECE) of lymph nodes are well-known major prognostic factors. However, there is no agreement on whether oral cavity cancer patients should receive postoperative chemo-radiotherapy (CCRT) if they present with other risk factors or a combination of 2 or more risk factors. In this study, we investigated this issue and provide suggestions for adjuvant treatments.From January 2002 to December 2013, 567 OSCC patients who had undergone radical surgery were retrospectively reviewed. The 5-year loco-regional control (LRC), distant metastasis-free (DMF), disease-free survival (DFS), and overall survival (OS) were analyzed.In univariate analysis, pathological T classification, positive node, tumor depth, ECE, lymphatic or vascular or perineural invasion and histology grade are significant prognostic factors for LRC, DMF, DFS, or OS. By multivariate analysis, pathological T4 (pT4), positive node, positive surgical margin are prognostic factors for LRC. pT4, positive node and lymphatic invasion predicted for higher rate of distant metastasis. pT4, positive node, and poor differentiation tumor were prognostic factors for DFS. pT4, positive nodes, and ECE were prognostic factors for OS. These factors were used to define risk groups. We proposed PRM and ECE as major risk factors and pT4, positive nodes, close margin (⩽ 5 mm, > 1 mm), tumor depth ≥ 1 cm, lymphatic invasion, vascular invasion, perineural invasion, and poor differentiation as minor risk factors. By subgroups analysis, 192 patients with at least 2 minor prognostic factors and no other major risk factors, postoperative radiotherapy (RT), or CCRT yielded significantly better 5-year LRC, DFS, and OS compared to surgery only group. For 179 patients with at least 3 minor prognostic factors and/or at least 1 major risk factor, patients receiving postoperative CCRT showed significantly better 5-year LRC, DFS, and OS compared with post-OP RT or surgery alone.Patients with 2 minor risk factors should receive postoperative RT. For patients with PRM, ECE, or >2 minor risk factors, postoperative CCRT is recommended.

Epigenetic therapy regulates the expression of ALDH1 and immunologic response: Relevance to the prognosis of oral cancer

OBJECTIVES Aldehyde dehydrogenase 1 (ALDH1) is associated with tumorigenesis, and shown to identify cancer stem cells (CSC)-like cells. We aimed to investigate the significance of ALDH1 in oral squamous cell carcinoma (OSCC) and its correlation with DNMT3b and immune evasion in the present study. METHODS We retrospectively analyzed the clinical outcomes of OSCC patients and examined its correlation with the levels of ALDH1 in tumors and circulating myeloid-derived suppressor cells (MDSCs) in the peripheral blood. Furthermore, the relationships between the DNMT3b, ALDH1 expression, and immune response were examined via clinical specimens and cellular and animal experiments. We also investigated the therapeutic potential of DNA hypomethylating agents in OSCC. RESULTS Our data revealed that the levels of ALDH1 expression were linked to treatment resistance, CSC-like properties, higher circulating MDSC and poor prognosis for OSCC. The radiation resistance noted in ALDH1-positive tumors was associated with augmented radiation-induced increases in the expression of programmed death ligand (PD-L1) and the activation of MDSCs. Furthermore, there was a positive link between ALDH1 and DNMT3b expression shown by clinical specimens and cellular experiments. DNA hypomethylating agents attenuated the radioresistance of ALDH1-positive cancer cells associated with the decreased ALDH1 and the increased DNA damages. In addition, the activation of MDSCs and the expression of PD-L1 were significantly attenuated by epigenetic therapy. CONCLUSIONS Our findings suggested that ALDH1 played an important role in treatment response and the tumor-promoting microenvironment in OSCC. Moreover, epigenetic therapy could be a promising strategy for the treatment of OSCC.

Mortality in tongue cancer patients treated by curative surgery: a retrospective cohort study from CGRD

Background Our study aimed to compare the outcomes of surgical treatment of tongue cancer patients in three different age groups. Methods From 2004 to 2013, we retrospectively analyzed the clinical data of 1,712 patients who were treated in the four institutions constituting the Chang Gung Memorial Hospitals (CGMH). We divided and studied the patients in three age groups: Group 1, younger (<65 years); Group 2, young old (65 to <75); and Group 3, older old patients (≥75 years). Results Multivariate analyses determined the unfavorable, independent prognostic factors of overall survival to be male sex, older age, advanced stage, advanced T, N classifications, and surgery plus chemotherapy. No significant differences were found in adjusted hazard ratios (HR) of death in early-stage disease (stage I–II) among Group 1 (HR 1.0), Group 2 (HR 1.43, 95% confidence interval (CI) [0.87–2.34], p = 0.158), and Group 3 (HR 1.22, 95% CI [0.49–3.03], p = 0.664) patients. However, amongst advanced-stage patients (stage (III–IV)), Group 3 (HR 2.53, 95% CI [1.46–4.38], p = 0.001) showed significantly worse survival than the other two groups after other variables were adjusted for. Fourteen out of 21 older old, advanced-staged patients finally died, and most of the mortalities were non-cancerogenic (9/14, 64.3%), and mostly occurred within one year (12/14, 85%) after cancer diagnosis. These non-cancer cause of death included underlying diseases in combination with infection, pneumonia, poor nutrition status, and trauma. Conclusions Our study showed that advanced T classification (T3–4), positive nodal metastasis (N1–3) and poorly differentiated tumor predicted poor survival for all patients. Outcome of early-stage patients (stage I–II) among three age groups were not significantly different. However, for advanced-stage patients (stage III–IV), the older old patients (≥75) had significantly worse survival than the other two patient groups. Therefore, for early-stage patients, age should not deny them to receive optimal treatments. However, older old patients (≥75) with advanced cancer should be comprehensively assessed by geriatric tools before surgical treatment and combined with intensive postoperative care to improve outcome, especially the unfavorable non-cancerogenic mortalities within one year after cancer diagnosis.

Estimation of life expectancy and quality-adjusted life expectancy in non-metastatic nasopharyngeal cancer patients treated by intensity-modulated radiotherapy with or without chemotherapy

PURPOSE This study was designed to estimate the life expectancy (LE) and quality-adjusted life expectancy (QALE) in non-metastatic nasopharyngeal cancer (NPC) patients. METHODS AND MATERIALS Patients were eligible for the present study if they were diagnosed with NPC and had been treated with intensity-modulated radiotherapy (IMRT) between January 1, 2003 and December 31, 2010. The quality of life (QOL) data were collected using the questionnaires of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-H&N35. The LE of NPC patients was obtained using linear extrapolation of a logit-transformed curve and was adjusted by the corresponding QOL function to calculate the QALE. RESULTS During the study period, 110 patients met the inclusion criteria, and 53 of these completed questionnaires. The median follow-up was 65.2 months (range 4.0-117.3 months). The average LE and QALE were estimated to be 20.6 years and 11.6 quality-adjusted life years (QALYs) for NPC patients and 24.4 years and 24.4 QALYs for the reference population, respectively. Compared to the reference population, the loss of LE and QALE for NPC patients were 3.8 years and 12.8 QALYs, respectively. CONCLUSIONS This study offers a quick overview of the LE and the QALE of NPC patients treated with IMRT. Moreover, the results appear more understandable than the 5 year survival outcomes when communicating with patients or the general population regarding cancer risk. In the future, evaluating the robustness of comparative assessments for the outcome of NPC patients undergoing different treatment protocols will be possible.

ANALYSIS OF PROGNOSTIC FACTORS OF ORAL CAVITY SQUAMOUS CELL CARCINOMA PATIENTS RECEIVING SURGERY

Purpose : Patients with oral cavity squamous cell carcinoma (OSCC) undergoing surgery were recommended to receive adjuvant radiotherapy (RT) with or without chemotherapy if there are unfavorable prognostic factors. Positive surgical margin and extracapsular extension (ECE) of lymph node were well-known major prognostic factors and adjuvant concurrent chemoradiotherapy (CCRT) was suggested for patients with these factors. However, the managements of patients with other risk factors were still debatable. In this study, we tried to recognize the minor risk factors and provide adjuvant treatment suggestions. Materials and Methods : From January 2002 to December 2013, 567 OSCC patients receiving radical surgery were retrospectively reviewed. Five-year locoregional control (LRC), disease free survival (DFS) and overall survival (OS) were analyzed by the Kaplan-Meier method. Univariate and multivariate analyses were used to identify the risk factors for LRC, DFS, and OS. Cox regression model was used for multivariate analyses. Results : The median follow-up time was 3.5 years (range: 0.2–12.5 years). The median age of the patients was 54 years old (range 28 to 79 years). The 5-year OS rate for stage I, II, III, IVa, IVb patients were 79.7%, 70.8%, 65.8%, 49.0%, and 17.7%, respectively. The 5-year DFS rate for stage I, II, III, IVa, IVb patients were 65.8%, 63.8%, 61.5%, 39.9% and 30.1%, respectively. The 5-year LRC rate for stage I, II, III, IVa, IVb patients were 77.6%, 77.6%, 76%, 67.8% and 42.5%, respectively. The pathological T-classification, pathological N-classification, ECE, pathological tumor depth, lymphatic invasion, perineural invasion, histology grading were prognostic factors for 5-year LRC, DFS and OS. Moreover, age and treatment modalities were prognostic factors for 5-year OS and age, performance status, vascular invasion and treatment modalities were prognostic factors for 5-year DFS, respectively. In subgroup analysis, 203 patients with at least two of poor prognostic factors and without positive margin nor ECE receiving RT with radiation dose at least 60 Gy showed better 5-year LRC (76.2% v.s 68.6%, p= 0.027) and DFS (56.1% v.s 44.1%, p= 0.05) and OS (63.9% v.s 50.4%, p= 0.021) than those without adjuvant RT or receiving RT with radiation dose less than 60 Gy. Conclusions : In addition to ECE and positive margin, pathological T-classification T4a/T4b, pathological positive node, pathological tumor depth ≧ 10 mm, lymphatic invasion, vascular invasion, perineural invasion and poorly differentiated grading were poor prognostic factors for LRC and survival outcomes for OSCC patients. Patients with two or more poor prognostic factors should receive radiotherapy with radiation dose at least 60 Gy.