Cheng-Fang Horng

Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma

PURPOSE To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure. RESULTS In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities. CONCLUSION Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.

Sublethal Irradiation Induces Vascular Endothelial Growth Factor and Promotes Growth of Hepatoma Cells: Implications for Radiotherapy of Hepatocellular Carcinoma

Purpose: To investigate the clinical benefit of additional radiotherapy to patients with unresectable hepatocellular carcinoma treated with transcatheter arterial chemoembolization (TACE) and the molecular effects of radiation on gene expression in hepatoma cells. Experimental Design: Between August 1996 and August 2003, 276 and 64 patients with American Joint Committee on Cancer stage T3N0M0 hepatocellular carcinoma receiving TACE alone and TACE followed by three-dimensional conformal radiotherapy, respectively, at our institution were studied. Clinical outcome and pattern of failure were analyzed for the association of survival benefit with radiotherapy. The molecular effects of radiotherapy were studied in vitro and in vivo using human hepatoma cells with different p53 mutation and hepatitis B virus infection status. Results: Median follow-up and survival time in the TACE alone and TACE + radiotherapy groups were 39 and 19 months, and 51 and 17 months, respectively. Additional radiotherapy to TACE did not improve overall survival (P = 0.65). However, different failure patterns were noted after TACE and after radiotherapy. Although all irradiated tumors regressed substantially, radiotherapy rapidly enhanced both intrahepatic and extrahepatic tumor progression outside the radiotherapy treatment field in a significant portion of patients, which offset the benefit of radiotherapy on overall survival. In molecular analysis of the radiation effects on human hepatoma cells, radiotherapy rapidly induced p53-independent transcriptional up-regulation of vascular endothelial growth factor (VEGF), increased VEGF secretion in a dose-, time-, and cell type–dependent manner, and promoted hepatoma cell growth in vivo with enhanced intratumor angiogenesis, which correlated well with elevated levels of serum VEGF. Conclusions: Radiotherapy to eradicate a primary hepatocellular carcinoma might result in the outgrowth of previously dormant microtumors not included in the radiotherapy treatment field. Radiotherapy-induced VEGF could be a paracrine proliferative stimulus. Therapeutic implications of the study justify the combination of three-dimensional conformal radiotherapy with anti-VEGF angiogenic modalities for the treatment of unresectable hepatocellular carcinoma to reduce relapses.

Adherence to Quality Indicators and Survival in Patients With Breast Cancer

Background:International initiatives increasingly advocate physician adherence to clinical protocols that have been shown to improve outcomes, yet the process-outcome relationship for adhering to breast cancer care protocol is unknown. Objective:This study explores whether 100% adherence to a set of quality indicators applied to individuals with breast cancer is associated with better survival. Research Design and Subjects:Ten quality indicators (4 diagnosis-related and 6 treatment-related indicators) were used to measure the quality of care in 1378 breast cancer patients treated from 1995 to 2001. Adherence to each indicator was based on the number of procedures performed divided by the number of patients eligible for that procedure. The main analysis of adherence was dichotomous (ie, 100% adherence vs. <100% adherence). Measures:The outcome measures studied were 5-year overall survival and progression-free survival, calculated using the Kaplan-Meier method. The Coxs proportional hazard regression model was used for univariate and multivariate analyses. Results:Most patients received care that demonstrated good adherence to the quality indicators. Multivariate analysis revealed that 100% adherence to entire set of quality indicators was significantly associated with better overall survival [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.33–0.63] and progression-free survival (HR 0.51; 95% CI, 0.39–0.67). One hundred percent adherence to treatment indicators alone was also associated with statistically significant improvements in overall and progression-free survivals. Conclusions:Our study strongly supports that 100% adherence to evidence supported quality-of-care indicators is associated with better survival rates for breast cancer patients and should be a priority for practitioners.

Rab5A is associated with axillary lymph node metastasis in breast cancer patients

The expression of Rab proteins has been associated with cancer. However, few data are available on Rab5A expression in human breast cancer or its impact on disease progression. First, we examined the functional role of Rab5A in breast cancer cells. The expression of Rab5A in MDA‐MB‐231 cells can be stimulated by epidermal growth factor in a dose‐dependent manner. The epidermal growth factor‐induced increase of Rab5A expression correlated well with enhanced migration in wound healing migration assays in these cells. Furthermore, we evaluated the expression of Rab5A in breast cancer specimens using immunohistochemical staining, then analyzed the relationship between the expression of Rab5A and clinicopathological parameters. The increased expression of Rab5A protein in 123 breast cancer samples was associated with higher histological grade (P = 0.004), more lymphovascular invasion (P = 0.027), more axillary lymph node (LN) metastasis (P = 0.008), and a higher number of axillary LN metastases (P = 0.043). Among 218 axillary LNs of more than 10 breast cancer patients with node metastases, 167 metastatic LNs were found to have increased Rab5A expression. Rab5A is associated with axillary LN metastasis in breast cancer patients. (Cancer Sci 2011; 102: 2172–2178)

Use of combined molecular biomarkers for prediction of clinical outcomes in locally advanced tonsillar cancers treated with chemoradiotherapy alone

Environmental exposures to tobacco, alcohol, human papillomavirus (HPV) and/or Epstein‐Barr virus (EBV), all of which can perturb multiple cell cycle proteins or tumor suppressors, have been implicated in the pathogenesis of different subsets of head and neck cancers. The aim of this study was to investigate to which extent the virus infection by itself, and/or the altered cell cycle proteins, contributes to prognosis in locally advanced tonsillar squamous cell carcinomas (TSCCs) treated with concurrent chemoradiotherapy (CCRT) alone.

Gene expression profiling in prognosis of distant recurrence in HR-positive and HER2-negative breast cancer patients

There had been several studies using gene-expression profiling in predicting distant recurrence in breast cancer. In this study, we developed an 18-gene classifier (18-GC) to predict distant recurrence of breast cancer and compared it with the 21-gene panel (Oncotype DX®, ODx) in performance. Included were 224 breast cancer patients with positive hormonal receptor (HR+) and negative human epidermal growth factor receptor 2 (HER2-). We compared the demographic, clinical, and survival information of the patients, and further compared the prediction of recurrence risk obtained by using the 18-GC with that by ODx. To have the best combined sensitivity and specificity, receiver operating characteristics (ROC) curve analysis was performed to determine the cutoff values for several breakpoint scores. For the new 18-GC, a breakpoint score of 21 was adopted to produce a combined highest sensitivity (95%) and specificity (39%) in detecting distant recurrence. At this breakpoint score, 164 of the 224 patients were classified by the 18-GC in the same risk level as by ODx, giving a concordance rate of 73%. Along with patient age and tumor stage, this 18-GC was found to be an independent significant prognostic factor of distant metastasis of breast cancer. We have thus created a new gene panel assay for prediction of distant recurrence in HR+ and HER2- breast cancer patients. With a high concordance rate with ODx, this new assay may serve as a good tool for individual breast cancer patients to make an informed decision on whether adjuvant chemotherapy should be performed post-surgery.

Survival without adjuvant chemotherapy for selected patients with stage II and III nasopharyngeal carcinoma after concurrent chemoradiotherapy alone

The role of adjuvant chemotherapy after concurrent chemoradiotherapy (CRT) for nasopharyngeal carcinoma (NPC) is controversial. We report our phase II prospective study of withholding adjuvant chemotherapy in a subgroup of patients with American Joint Committee on Cancer (AJCC) stage II and III NPC with low risk for metastasis.

Late Recurrences in Luminal-Like Breast Cancer

Purpose: The intention of this study is to both examine the disease entity and late recurrences of luminal-like (hormonal receptor positive and HER2-negative) breast cancer, and identify the prognostic factors associated with disease recurrences. Materials and Methods: We selected for this study breast cancer patients initially treated with primary surgeries in our institution between 1990 and 2007, who also fit the following criteria: 1) pathology stage I-III, 2) hormonal receptor-positive, and 3) HER2/neu-negative. Out of the total 1763 eligible patients, 1275 (72%) received adjuvant chemotherapy, 937 (53%) underwent radiotherapy, and 1629 (92%) had hormonal therapy. Cox proportional hazards regression models were used to assess the prognostic significance of the risk factors related to disease recurrences. Results: The five- and ten-year disease-free survival rates were 96% and 91% for stage I patients, 90% and 81% for stage II, and 79% and 65% for stage III patients, respectively. The incidence of recurrence at each stage in the first 5 years was almost equal to that in the second 5 years. The independent risk factors, according to the multivariate analysis, were: age ≤ 40 (hazard ratio [HR] 1.8, 95% confidence interval [CI], 1.4-2.5); tumor ＞ 2cm (HR 1.6, 95% CI, 1.1-2.1); axillary lymph node positive (HR 1.9/2.0/3.9, 95% CI, 1.3-2.8/1.2-3.4/2.2-6.8 for node positive 1-3/4-9/≥10, respectively); nuclear grade III (HR 1.4, 95% CI, 1.1-1.9); the presence of ECS (HR 1.6, 95% CI, 1.1-2.30); and adjuvant hormonal therapy (HR 0.48, 95% CI, 0.30-0.76). Conclusions: Luminal-like (hormonal receptor positive and HER2-negative) breast cancer has excellent long-term outcomes, but also has a considerable frequency of late recurrences. The risk of breast cancer recurrence is relatively high for patients ≤ 40 years of age, with tumor size greater than 2cm, with axillary LN metastasis, status of nuclear grade III, or with ECS involvement. Clinical trials should be considered for these high-risk breast cancer patients, especially for patients who are diagnosed at 40 years of age or younger.

The Comparison of Nodal Stage Determined by Magnetic Resonance Imaging and Clinical Palpation for Nasopharyngeal Carcinoma Patients with Bulky Lymph Node Metastasis

Purpose: This study is to find out whether maximal lymph node size determined by magnetic resonance imaging (MRI) correlates with prognosis better than that determined by clinical palpation for patients with nasopharyngeal carcinoma (NPC) and bulky cervical lymph node metastasis. Material and Methods: All eligible NPC patients should have cervical lymph node size 6 cm or greater by clinical palpation and use MRI as primary imaging modality. Patients with N3b and distant metastases were excluded from this study. From 1992 to 2005, a total of 47 patients were included. Their MRI nodal stage was determined at weekly multidisciplinary team conference with a consensus. Patients received concurrent chemoradiotherapy with or without adjuvant chemotherapy according to hospital guideline. We compared the survival and failure patterns of MRI N1-2 and MRI N3a patients. Results: Twenty-two patients were assigned MRI N3a and 25 MRI N1 or N2. With a median follow up of 64 months, the 5-year disease-free survival rate for MRI N3a group (53%) was lower than MRI N1-2 group (65%) but not statistically significant (p=0.56). The 5-year overall survival and metastasis-free survival of MRI N3a vs MRI N1-2 patients were 78% vs. 77% (p= 0.5) and 70% vs. 65% (p= 0.9), respectively. The failure pattern was similar. Conclusion: NPC patients with clinical bulky cervical lymph node metastasis have relatively poor survival regardless of MRI N-stage. We recommend that if cervical lymph nodes are confluent together, their sizes determined by MRI should not be measured separately. These patients are best to be staged as N3a disease.