Shiang-Jiun Tsai

Higher caseload improves cervical cancer survival in patients treated with brachytherapy

ObjectivesIncreased caseload has been associated with better patient outcomes in many areas of health care, including high-risk surgery and cancer treatment. However, such a positive volume vs. outcome relationship has not yet been validated for cervical cancer brachytherapy. The purpose of this study was to examine the relationship between physician caseload and survival rates in cervical cancer treated with brachytherapy using population-based data.MethodsBetween 2005 and 2010, a total of 818 patients were identified using the Taiwan National Health Insurance Research Database. Multivariate analysis using a Cox proportional hazards model and propensity scores was used to assess the relationship between 5-year survival rates and physician caseloads.ResultsAs the caseload of individual physicians increased, unadjusted 5-year survival rates increased (P = 0.005). Using a Cox proportional hazard model, patients treated by high-volume physicians had better survival rates (P = 0.03), after adjusting for comorbidities, hospital type, and treatment modality. When analyzed by propensity score, the adjusted 5-year survival rate differed significantly between patients treated by high/medium-volume physicians vs. patients treated by low/medium-volume physicians (60% vs. 54%, respectively; P = 0.04).ConclusionsProvider caseload affected survival rates in cervical cancer patients treated with brachytherapy. Both Cox proportional hazard model analysis and propensity scores showed association between high/medium volume physicians and improved survival.

High Incidence of Ischemic Stroke Occurrence in Irradiated Lung Cancer Patients: A Population-Based Surgical Cohort Study

Background and Purpose A high risk of stroke occurrence has been reported in several types of irradiated cancer patients. However, clinical data are lacking in irradiated lung cancer patients. The present study intended to explore a risk level of ischemic stroke occurrence in irradiated lung cancer patients. Methods A nationwide population-based database obtained from the Taiwan National Health Insurance was analyzed. Between 2003 and 2006, we recruited 560 resected lung cancer patients into two study groups: surgery-plus-irradiation (n = 112) and surgery-alone (n = 448). Patients treated with chemotherapy were excluded. Propensity score match was used for pairing cases with a ratio of 1∶4. Two-year ischemic-stroke-free survival was defined as the primary endpoint. Results Three observations supported a high risk of ischemic stroke occurrence in patients with postoperative irradiation when compared with those patients with surgery alone: first, a high incidence per 1,000 person-year (22.3 versus 11.2, 1.99 folds); second, a low two-year ischemic-stroke-free survival rate (92.2% versus 98.1%, P = 0.019); and third, a high adjusted hazard ratio (HR, 4.19; 95% CI, 1.44–12.22; P = 0.009). More notably, the highest risk of ischemic stroke occurrence was found in irradiated patients who had diabetes mellitus (HR, 34.74; 95% CI, 6.35->100; P<0.0001). Conclusions A high incidence of ischemic stroke was observed in irradiated lung cancer patients, especially in those with diabetes mellitus. For these patients, close clinical surveillance and strict diabetes control should be considered. Further studies to define detail biological mechanisms are encouraged.

Better Survival with Three-Dimensional Conformal Radiotherapy Than with Conventional Radiotherapy for Cervical Cancer: A Population-Based Study

Three-dimensional conformal radiation therapy (3DCRT) has emerged as a preferred treatment for gynecologic malignancies. Yet its superiority to conventional radiotherapy (2-dimensional radiotherapy (2DRT)) for gynecologic malignancies has not been well established. Data from the 2005 to 2010 National Health Insurance Research Database (NHIRD) provided by the National Research Institutes in Taiwan were analyzed to address this issue. Patients were initially diagnosed as having cervical cancer according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) code 180, and this clinical diagnosis was confirmed histopathologically or cytologically. Kaplan-Meier method and Cox proportional hazards regression were used to analyze the reported data. Between January 2005 and December 2010, there were 776 patients with newly diagnosed cervical cancer without metastasis, local recurrence, or surgical treatment before RT and 132 and 644 patients, respectively, who received 2DRT and 3DCRT. After adjustment for age, diabetes mellitus, hypertension, coronary heart disease, hyperlipidemia, side effects, urbanization level, geographic region, and enrollee category in the 5-year follow-up period, the HR was 1.82 (95% CI, 1.16–2.85, P = 0.009). The 5-year survival rate in the 2DRT and 3DCRT groups was 73.0% and 82.3%, P = 0.007, respectively. Cervical cancer patients treated with 3DCRT had better overall survival.

The incidence of venous thromboembolism in cervical cancer: a nationwide population-based study

BackgroundVenous thromboembolism (VTE) is a life-threatening condition that occurs as a complication of cervical cancer. The aim of this study was to evaluate the incidence of VTE in cervical cancer patients during a 5-year follow-up.MethodsThe study analyzed data deposited between 2003 and 2008 in the National Health Insurance Research Database (NHIRD), provided by the National Health Research Institutes in Taiwan. Totally, 1013 cervical cancer patients after treatment and 2026 appendectomy patients were eligible. The Kaplan-Meier method and the Cox proportional hazards model were used to assess the VTE risk.ResultsThe 5-year cumulative risk for VTE was significantly higher in the cervical cancer group than in the control group (3.3% vs 0.3%, p < 0.001). The hazard ratio for VTE was 10.14 times higher in the cervical cancer group than in the controls. The combined presence of more comorbidities was associated with a higher risk for VTE. Furthermore, cervical cancer patients without VTE had a significantly higher survival (75.3% vs 30.3%, p < 0.001).ConclusionsThe cumulative risk of VTE was significantly higher in cervical cancer patients, and these patients also had lower survival rates. Strategies to reduce these risks need to be examined.

Significant symptoms alleviation and tumor volume reduction after combined simultaneously integrated inner-escalated boost and volumetric-modulated arc radiotherapy in a patient with unresectable bulky hepatocellular carcinoma: A care-compliant case report.

Background:Clinically, elderly patients with unresectable bulky hepatocellular carcinoma (HCC) are difficult to manage, especially in those with co-infections of hepatitis B and C virus. Herein, we reported such a case treated with radiotherapy (RT) by using combined simultaneously integrated inner-escalated boost and volumetric-modulated arc radiotherapy (SIEB-VMAT). After RT, significant symptoms alleviation and durable tumor control were observed. Case Summary:At presentation, an 85-year-old male patient complained abdominal distention/pain, poor appetite, and swelling over bilateral lower limbs for 1 month. On physical examination, a jaundice pattern was noted. Laboratory studies showed impaired liver and renal function. Abdominal computed tomography (CT) revealed a 12.5-cm bulky tumor over the caudate lobe of the liver. Biopsy was done, and hepatocellular carcinoma (HCC) was reported histopathologically. As a result, AJCC stage IIIA (cT3aN0M0) and BCLC stage C were classified. Surgery, radiofrequency ablation (RFA), trans-catheter arterial chemoembolization (TACE), and sorafenib were not recommended because of his old age, central bulky tumor, and a bleeding tendency. Thus, RT with SIEB-VMAT technique was given alternatively. RT was delivered in 26 fractions, with dose gradience as follows: 39 Gy on the outer Plan Target Volume (PTV), 52 Gy in the middle PTV, and 57.2 Gy in the inner PTV. Unexpectedly, cyproheptadine (a newly recognized potential anti-HCC agent) was retrospectively found to be prescribed for alleviating skin itching and allergic rhinitis since the last 2 weeks of the RT course (2 mg by mouth Q12h for 24 months).After RT, significant symptoms alleviation and tumor volume reduction were observed for 32 months till multiple bone metastases. Before and after RT, a large tumor volume reduction rate of 88.7% was observed (from 608.4 c.c. to 68.7 c.c.). No severe treatment toxicity was noted during and after RT. The patient died due to aspiration pneumonia with septic shock at 4 months after bone metastases identified. Conclusions:SIEB-VMAT physically demonstrated double benefits of intratumor dose escalation and extra-tumor dose attenuation. Significant tumor regression and symptoms alleviation were observed in this elderly patient with unresectable bulky HCC. Further prospective randomized trials are encouraged to demarcate effective size of SIEB-VMAT with or without cyproheptadine.

Risk of rheumatoid arthritis in patients with hepatitis C virus infection receiving interferon-based therapy: a retrospective cohort study using the Taiwanese national claims database

Objectives To illuminate the association between interferon-based therapy (IBT) and the risk of rheumatoid arthritis (RA) in patients infected with hepatitis C virus (HCV). Design, setting, participants and interventions This retrospective cohort study used Taiwan’s Longitudinal Health Insurance Database 2005 that included 18 971 patients with HCV infection between 1 January 1997 and 31 December 2012. We identified 1966 patients with HCV infection who received IBT (treated cohort) and used 1:4 propensity score-matching to select 7864 counterpart controls who did not receive IBT (untreated cohort). Outcome measures All study participants were followed until the end of 2012 to calculate the incidence rate and risk of incident RA. Results During the study period, 305 RA events (3.1%) occurred. The incidence rate of RA was significantly lower in the treated cohort than the untreated cohort (4.0 compared with 5.5 per 1000 person-years, p<0.018), and the adjusted HR remained significant at 0.63 (95% CI 0.43 to 0.94, p=0.023) in a Cox proportional hazards regression model. Multivariate stratified analyses revealed that the attenuation in RA risk was greater in men (0.35; 0.15 to 0.81, p=0.014) and men<60 years (0.29; 0.09 to 0.93, p=0.036). Conclusions This study demonstrates that IBT may reduce the risk of RA and contributes to growing evidence that HCV infection may lead to development of RA.

Effectiveness of 23-valent pneumococcal polysaccharide vaccine on elderly long-term cancer survivors: a population-based propensity score matched cohort study

Objective The Advisory Committee on Immunization Practices in 2012 recommended the 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults with high risk of pneumonia. However, its effectiveness in cancer survivors has not been investigated. Our aim was to investigate the effectiveness of PPSV23 in these patients. Design Population-based matched cohort study. Setting Claim data were obtained from 1 million people registered with the National Health Insurance Research Database in 1996, and followed to 2010. People aged ≥75 years are eligible for receiving PPSV23 vaccination in Taiwan since 2007. Participants Among the 30 249 patients with cancer, 6784 patients were 75 years or older eligible for PPSV23 vaccination. Among them, 1887 survived 5 or more years (ie, cancer survivors) after cancer diagnosis. We identified 377 cancer survivors who received PPSV23. A total of 754 propensity score matched unvaccinated patients were randomly selected. Intervention PPSV23 vaccination. Primary outcome measures The primary outcome was pneumonia hospitalisation. Potential confounders include influenza vaccination, vaccination period, cancer treatment modalities, comorbidities and sociodemographic variables. Results After 2 years of follow-up, vaccinated patients had a significantly lower incidence rate of pneumonia hospitalisation at 73.66 per 1000 person-years (PYs), compared with 117.82 per 1000 PYs for unvaccinated patients. Additionally, the prevalence for pneumonia hospitalisation frequency of >0–1,>1–2,>2–3 and >3 times per PY was all consistently lower in the vaccinated group (6.63% vs 9.28%, 1.86% vs 2.52%, 0.80% vs 1.59% and 0.27% vs 0.53%, respectively). After adjustment for covariates, PPSV23 vaccine was significantly associated with reduced pneumonia hospitalisation risk, with an adjusted incidence rate ratio of 0.695 (p=0.030). While the cumulative pneumonia incidence was also significantly lower in the vaccinated patients (p=0.027), the overall survival time was similar (p=0.136). Conclusions PPSV23 vaccination was associated with a significantly reduced rate of pneumonia hospitalisation in long-term cancer survivors.

Irradiation enhanced risks of hospitalised pneumonopathy in lung cancer patients: a population-based surgical cohort study

Objective Pulmonary radiotherapy has been reported to increase a risk of pneumonopathy, including pneumonitis and secondary pneumonia, however evidence from population-based studies is lacking. The present study intended to explore whether postoperative irradiation increases occurrence of severe pneumonopathy in lung cancer patients. Design, setting and participants The nationwide population-based study analysed the Taiwan National Health Insurance Research Database (covered >99% of Taiwanese) in a real-world setting. From 2000 to 2010, 4335 newly diagnosed lung cancer patients were allocated into two groups: surgery-RT (n=867) and surgery-alone (n=3468). With a ratio of 1:4, propensity score was used to match 11 baseline factors to balance groups. Interventions/exposure(s) Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines. Outcome(s)/measure(s) Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures. Results Multivariable analysis identified five independent risk factors for hospitalised pneumonopathy: elderly (>65 years), male, irradiation, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Compared with surgery-alone, a higher risk of hospitalised pneumonopathy was found in surgery-RT patients (HR, 2.20; 95% CI, 1.93–2.51; 2-year hospitalised pneumonia/pneumonitis-free survival, 85.2% vs 69.0%; both p<0.0001), especially in elderly males with COPD and CKD (HR, 13.74; 95% CI, 6.61–28.53; p<0.0001). Unexpectedly, we observed a higher risk of hospitalised pneumonopathy in younger irradiated-CKD patients (HR, 13.07; 95% CI, 5.71–29.94; p<0.0001) than that of elderly irradiated-CKD patients (HR, 4.82; 95% CI, 2.88–8.08; p<0.0001). Conclusions A high risk of hospitalised pneumonopathy is observed in irradiated patients, especially in elderly males with COPD and CKD. For these patients, close clinical surveillance and aggressive pneumonia/pneumonitis prevention should be considered. Further investigations are required to define underlying biological mechanisms, especially for younger CKD patients.

Implementing web-based ping-pong-type e-communication to enhance staff satisfaction, multidisciplinary cooperation, and clinical effectiveness: A SQUIRE-compliant quality-improving study

Background:Frequent multidisciplinary communication is essential in conducting daily radiotherapy (RT) practice. However, traditional oral or paper-based communication has limitations. E-communication has been suggested, but its effects are still not well demarcated in the field of radiation oncology. Objects:In our web-based integrated information platform, we constructed a ping-pong-type e-communication function to transfer specific notations among multidisciplinary RT staffs. The purpose was to test whether applying this e-communication can increase effectiveness of multidisciplinary cooperation when compared with oral or paper-based practice. Staff satisfaction and clinical benefits were also demonstrated. Design and setting:A real-world quality-improving study was conducted in a large center of radiation oncology. Participants and dataset used:Before and after applying multidisciplinary e-communication (from 2014 to 2015), clinical RT staffs were surveyed for their user experience and satisfaction (n = 23). For measuring clinical effectiveness, a secondary database of irradiated head and neck cancer patients was re-analyzed for comparing RT toxicities (n = 402). Interventions:Applying ping-pong-type multidisciplinary reflective e-communication was the main intervention. Outcome measures:For measuring staff satisfaction, eight domains were surveyed, such as timeliness, convenience, and completeness. For measuring clinical effectiveness of multidisciplinary cooperation, event rates of severe (i.e., grade 3–4) RT mucositis and dermatitis were recorded. Results:Overall, when compared with oral communication only, e-communication demonstrated multiple benefits, particularly on notation-review convenience (2.00 ± 1.76 vs 9.19 ± 0.81; P < 0.0001).When compared with paper-based practice, e-communication showed statistically significant benefits on all eight domains, especially on notation-review convenience (5.05 ± 2.11 vs 9.19 ± 0.81; P < 0.0001) and convenience of feedback notation (4.81 ± 1.72 vs 8.76 ± 1.09; P < 0.0001).Moreover, staff satisfaction was gradually increased from oral (3.57 ± 1.94), paper-based (5.57 ± 2.06), to e-communication (8.76 ± 0.70; P < 0.0001). Secondary measurement confirmed these observations.Before and after facilitating multidisciplinary cooperation by using e-communication, severe (i.e., grade 3–4) mucositis and dermatitis were decreased from 21.7% to 10% then to 5.1%. Conclusions:Replacing oral or paper-based practice with e-communication is useful in facilitating RT multidisciplinary teamwork. Staff satisfaction and clinical effectiveness can be increased.

Abstract 3314: DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer and its implication in treatment and outcome prediction

Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using Illumina 27K methylation BeadChip microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation (5-Gy by 10 fractions) of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation and H3K27me3 as demonstrated by MBDcap-PCR, bisulfite pyrosequencing and ChIP-PCR. These phenomenon were partially attributed to overexpression of EZH2 and DNMT3a, 3b in OML1-R cells. In consistent with these observations, treatment of 5-azaDC, EZH2 inhibitor (GSK343) or depletion of EZH2 by lentiviral knockdown restored FHIT expression in OML1-R cells. Interestingly, knockdown of EZH2 also reversed histone modifications (increased of H3K4me3 and decreased of H3K27me3) and reduced promoter methylation of FHIT thus suggesting that H3K27me3 linked to DNA methylation in this loci. We also analyzed the expression of FHIT in primary human oral keratinocyte (HOK) and four other oral cancer cell lines (OCSL, SCC25, SAS, and SCC4). FHIT expression demonstrated a tight inverse relationship with its promoter methylation. Ectopic expression of FHIT restored radiosensitivity (single fraction, 10-Gy) in OML1-R cells and oral cancer cells (SAS, SCC25) showing epigenetic silencing of FHIT. These phenomenon may be due to restoration of Chk2 phosphorylation, induction of apoptosis and G2/M check point. Reciprocal experiments also showed that depletion of FHIT in OSCL cells, which highly express FHIT, slightly enhanced radioresistance. Clinically, bisulfite pyrosequencing and iummnohistochemistry revealed that promoter hypermethylation of FHIT inversely correlated with its expression. Patients with higher FHIT methylation (methylation>10%, n = 22) are associated with lower locoregional control (P Citation Format: Hon-Yi Lin, Shih-Kai Hung, Moon-Sing Lee, Wen-Yen Chiou, Tze-Ta Huang, Chih-En Tseng, Liang-Yu Shih, Ru-Inn Lin, Jora Lin, Yi-Hui Lai, Chia-Bin Chang, Feng-Chun Hsu, Liang-Cheng Chen, Shiang-Jiun Tsai, Yu-Chieh Su, Szu-Chi Li, Hung-Chih Lai, Wen-Lin Hsu, Dai-Wei Liu, Chien-Kuo Tai, Shu-Fen Wu, Michael W. Chan. DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer and its implication in treatment and outcome prediction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3314. doi:10.1158/1538-7445.AM2015-3314