Kang-Hsing Fan

Staging of untreated nasopharyngeal carcinoma with PET/CT: comparison with conventional imaging work-up

PurposeWe prospectively compared PET/CT and conventional imaging for initial staging of nasopharyngeal carcinoma (NPC).MethodsA total of 111 patients with histologically proven NPC were investigated with PET/CT and conventional imaging (head-and-neck MRI, chest X-ray, abdominal ultrasound, and bone scan) before treatment. The respective findings were reviewed independently and then compared with each other.ResultsWith regard to T staging, PET/CT showed a discrepancy with head-and-neck MRI in 36 (32.4%) of the study subjects. With regard to N staging, PET/CT showed a discrepancy with head-and-neck MRI in 15 (13.5%) patients. Among the discordant cases, MRI was superior in demonstrating tumor involvement in the parapharyngeal space, skull base, intracranial area, sphenoid sinus, and retropharyngeal nodes while PET/CT was superior in demonstrating neck nodal metastasis. PET/CT disclosed 13 of 16 patients with distant malignancy compared with four patients disclosed by conventional imaging work-up. The false-positive rate of PET/CT was 18.8%. PET/CT correctly modified M staging in eight patients (7.2%) and disclosed a second primary lung malignancy in one patient (0.9%).ConclusionIn NPC patients, MRI appears to be superior to PET/CT for the assessment of locoregional invasion and retropharyngeal nodal metastasis. PET/CT is more accurate than MRI for determining cervical nodal metastasis and should be the better reference for the neck status. PET/CT has an acceptable diagnostic yield and a low false-positive rate for the detection of distant malignancy and can replace conventional work-up to this aim. PET/CT and head-and-neck MRI are suggested for the initial staging of NPC patients.

Neck treatment of patients with early stage oral tongue cancer : comparison between observation, supraomohyoid dissection, and extended dissection

The role of elective and therapeutic selective neck dissection in patients with early stage cancer of the oral tongue remains controversial. The purpose was to investigate the role of neck treatment in the management of this condition.

Human papillomavirus-16 infection in advanced oral cavity cancer patients is related to an increased risk of distant metastases and poor survival.

Background Human papillomavirus (HPV) is an oncogenic virus causing oropharyngeal cancers and resulting in a favorable outcome after the treatment. The role of HPV in oral cavity squamous cell carcinoma (OSCC) remains ambiguous. Objective This study aimed to examine the effect of HPV infection on disease control among patients with OSCC following radical surgery with radiation-based adjuvant therapy. Patients and Method We prospectively followed 173 patients with advanced OSCC (96% were stage III/IV) who had undergone radical surgery and adjuvant therapy between 2004 and 2006. They were followed between surgery and death or up to 60 months. Surgical specimens were examined using a PCR-based HPV blot test. The primary endpoints were the risk of relapse and the time to relapse; the secondary endpoints were disease-free survival, disease-specific survival, and overall survival. Results The prevalence of HPV-positive OSCC was 22%; HPV-16 (9%) and HPV-18 (7%) were the genotypes most commonly encountered. Solitary HPV-16 infection was a poor predictor of 5-year distant metastases (hazard ratio, 3.4; 95% confidence interval, 1.4–8.0; P = 0.005), disease-free survival (P = 0.037), disease-specific survival (P = 0.006), and overall survival (P = 0.010), whereas HPV-18 infection had no impact on 5-year outcomes. The rate of 5-year distant metastases was significantly higher in the HPV-16 or level IV/V metastasis group compared with both the extracapsular spread or tumor depth ≥11-mm group and patients without risk factors (P<0.001). Conclusions HPV infections in advanced OSCC patients are not uncommon and clinically relevant. Compared with HPV-16-negative advanced OSCC patients, those with a single HPV-16 infection are at higher risk of distant metastases and poor survival despite undergoing radiation-based adjuvant therapy and require a more aggressive adjuvant treatment and a more thorough follow-up.

Neck dissection field and lymph node density predict prognosis in patients with oral cavity cancer and pathological node metastases treated with adjuvant therapy

Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy. We examined 309 pN+ patients who underwent levels I-III ND and 148 pN+ patients treated with levels I-V ND. The 5-year control and survival rates served as the main outcome measures. The 5-year rates for patients treated with levels I-III and I-V NDs were as follows: local control, 79%, 74% (p=0.0630); neck control, 81%, 68% (p=0.0014); distant metastasis, 21%, 36% (p=0.0003); disease-free survival (DFS), 59%, 43% (p=0.0001); disease-specific survival (DSS), 66%, 46% (p<0.0001); and overall survival (OS), 49%, 37% (p=0.0048), respectively. Multivariate analysis demonstrated that an LN density ≥0.16 was an independent prognostic factor for 5-year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412-5.128]), distant metastases (0.001, 2.831 [1.520-5.270]), DFS (<0.001, 2.464 [1.571-3.866]), and DSS (0.036, 1.781 [1.040-3.052]) in levels I-III ND patients. An LN density ≥0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654-14.344]), neck control (0.002, 24.738 [3.367-181.771]), DFS (<0.001, 4.151 [2.264-7.610]), DSS (<0.001, 3.791 [2.017-7.125]), and OS (<0.001, 2.806 [1.706-4.613]) in levels I-V ND patients. Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy.

The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity

BackgroundThe aim of this study was to compare the outcomes of postoperative adjuvant concomitant chemoradiotherapy using two different schedules of cisplatin for patients with high-risk oral squamous cell carcinoma (OSCC).MethodsFrom Feb. 2008 to Aug. 2010, 55 patients with high-risk OSCC were included in this study. Patients were randomized into treatment groups that either received 100 mg/m2 cisplatin once every 3 weeks (arm A) or 40 mg/m2 cisplatin once per week (arm B). All patients were irradiated with 66 Gy in 33 fractions.ResultsOf the 50 eligible patients, 26 were assigned to arm A, and 24 were assigned to arm B. Both groups of patients received the same mean doses of radiotherapy and cisplatin. However, 88.5% of patients in arm A and 62.5% of those in arm B (p = 0.047) received ≥ 200 mg/m2 of cisplatin in total. The overall toxicity was significantly greater in arm B (p = 0.020), and all of the grade 4 toxicities occurred in patients in arm B.ConclusionsThree-weekly high-dose cisplatin treatment showed higher compliance, and lower acute toxicity compared to weekly low-dose cisplatin treatment.

PET and PET/CT of the Neck Lymph Nodes Improves Risk Prediction in Patients with Squamous Cell Carcinoma of the Oral Cavity

We prospectively evaluated the sensitivity and specificity of 18F-FDG PET in the detection of neck lymph node metastases in patients with oral cavity squamous cell carcinoma (OSCC). We also sought to evaluate whether pretreatment PET visual scores in the neck lymph nodes may improve risk stratification. Methods: We enrolled 473 OSCC patients (445 men and 28 women; mean age ± SD, 50.9 ± 11.7 y) without distant metastases. All participants underwent 18F-FDG PET within 2 wk before surgery and neck dissection. Histopathology was taken as the reference standard for neck lymph node status. The duration of follow-up was at least 24 mo in all surviving patients. Results: 18F-FDG PET correctly diagnosed 164 of 211 patients with neck metastases and 152 of 262 subjects without pathologic neck metastases, resulting in a patient-based sensitivity and specificity of 77.7% and 58.0%, respectively. In Cox models adjusting for age, sex, traditional risk factors, and treatment modality, PET results at the neck lymph nodes were significantly and independently associated with rates of neck control, distant metastasis, disease-free survival, disease-specific survival, and overall survival. Notably, the results of the c-statistics demonstrated that PET score improved the accuracy of risk prediction in terms of overall and disease-free survival rates. Conclusion: PET findings at the neck lymph nodes have limited sensitivity and specificity for primary staging of OSCC but improve risk stratification beyond that of traditional risk factors.

Treatment Results of Postoperative Radiotherapy on Squamous Cell Carcinoma of the Oral Cavity: Coexistence of Multiple Minor Risk Factors Results in Higher Recurrence Rates

PURPOSE The aim of this study was to investigate the treatment results of postoperative radiotherapy (PORT) on squamous cell carcinoma of the oral cavity (OSCC). MATERIALS AND METHODS This study included 302 OSCC patients who were treated by radical surgery and PORT. Indications for PORT include Stage III or IV OSCC according to the 2002 criteria of the American Joint Committee on Cancer, the presence of perineural invasion or lymphatic invasion, the depth of tumor invasion, or a close surgical margin. Patients with major risk factors, such as multiple nodal metastases, a positive surgical margin, or extracapsular spreading, were excluded. The prescribed dose of PORT ranged from 59.4 to 66.6 Gy (median, 63 Gy). RESULTS The 3-year overall and recurrence-free survival rates were 73% and 70%, respectively. Univariate analysis revealed that differentiation, perineural invasion, lymphatic invasion, bone invasion, location (hard palate and retromolar trigone), invasion depths > or =10mm, and margin distances < or =4mm were significant prognostic factors. The presence of multiple significant factors of univariate analysis correlated with disease recurrence. The 3-year recurrence-free survival rates were 82%, 76%, and 45% for patients with no risk factors, one or two risk factors, and three or more risk factors, respectively. After multivariate analysis, the number of risk factors and lymphatic invasion were significant prognostic factors. CONCLUSION PORT may be an adequate adjuvant therapy for OSCC patients with one or two risk factors of recurrence. The presence of multiple risk factors and lymphatic invasion correlated with poor prognosis, and more aggressive treatment may need to be considered.

Proteomics of the Radioresistant Phenotype in Head-and-Neck Cancer: Gp96 as a Novel Prediction Marker and Sensitizing Target for Radiotherapy

PURPOSE Radiotherapy is an integral part of the treatment modality for head-neck cancer (HNC), but in some cases the disease is radioresistant. We designed this study to identify molecules that may be involved in this resistance. METHODS AND MATERIALS Two radioresistant sublines were established by fractionated irradiation of the HNC cell lines, to determine differentially proteins between parental and radioresistant cells. Proteomic analysis and reverse-transcription polymerase chain reaction were used to identify and confirm the differential proteins. The siRNA knockdown experiments were applied to examine cellular functions of a radioresistant gene, with investigation of the alterations in colonogenic survival, cell cycle status, and reactive oxygen species levels. Xenografted mouse tumors were studied to validate the results. RESULTS IN all, 64 proteins were identified as being potentially associated with radioresistance, which are involved in several cellular pathways, including regulation of stimulus response, cell apoptosis, and glycolysis. Six genes were confirmed to be differentially expressed in both radioresistant sublines, with Gp96, Grp78, HSP60, Rab40B, and GDF-15 upregulated, and annexin V downregulated. Gp96 was further investigated for its functions in response to radiation. Gp96-siRNA transfectants displayed a radiation-induced growth delay, reduction in colonogenic survival, increased cellular reactive oxygen species levels, and increased proportion of the cells in the G2/M phase. Xenograft mice administered Gp96-siRNA showed significantly enhanced growth suppression in comparison with radiation treatment alone (p = 0.009). CONCLUSIONS We identified 64 proteins and verified 6 genes that are potentially involved in the radioresistant phenotype. We further demonstrated that Gp96 knockdown enhances radiosensitivity both in cells and in vivo, which may lead to a better prognosis of HNC treatment.

Clinical evidence of field cancerization in patients with oral cavity cancer in a betel quid chewing area

OBJECTIVES We sought to investigate whether there is evidence of field cancerization in patients with oral cavity squamous cell carcinoma (OSCC) enrolled in a betel quid chewing area. We also assessed whether betel quid chewing is an independent risk factor for field cancerization in OSCC patients. METHODS We retrospectively examined the records of 1570 OSCC patients who underwent radical tumor resection between 1996 and 2011. A total of 1243 study participants (79%) had a positive history of betel quid chewing before surgery. Of the 767 patients treated with surgery alone, 599 (78%) were preoperative chewers, whereas a history of preoperative betel quid chewing was identified in 644 (80%) of the 803 patients who received adjuvant therapy. The 5-year control, survival, and second primary tumors (SPTs) rates served as the main outcome measures. RESULTS Regardless of the treatment modality, more than 70% of the SPTs were located in the oral cavity or soft palate. Despite a similar risk profile in terms of tumor depth, lymph node metastasis, and pathological margin status, preoperative chewers showed a significantly higher incidence of 5-year SPTs and local recurrences compared with non-chewers. Moreover, multivariate analysis demonstrated that preoperative betel quid chewing was an independent prognostic factor for 5-year local control and SPTs occurrence rates. CONCLUSIONS Our results demonstrate that preoperative betel quid chewers had a higher incidence of local recurrence and SPTs than non-chewers, suggesting that field cancerization may occur in OSCC patients with a history of betel quid chewing.

Outcome Analysis of Patients With Oral Cavity Cancer and Extracapsular Spread in Neck Lymph Nodes

PURPOSE Extracapsular spread (ECS) in neck lymph nodes is a major adverse prognostic factor in patients with oral cavity squamous cell carcinoma (OSCC). We conducted a retrospective analysis of prognostic factors in this patient group and tried to identify a subset of patients with a worse prognosis suitable for more aggressive therapeutic interventions. METHODS AND MATERIALS Enrolled in the study were 255 OSCC patients with ECS in neck nodes and without evidence of distant metastasis. All participants were followed-up for at least 2 years or censored at last follow-up. The 5-year rates of control, distant metastasis, and survival were the main outcome measures. RESULTS Level IV/V lymph node metastases and tumor depth ≥12 mm were independent predictors of 5-year survival and identified three prognostic groups. In the low-risk group (no level IV/V metastases and tumor depth <12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 60%, 66%, and 50%, respectively. In the intermediate-risk group (no level IV/V metastases and tumor depth ≥12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 39%, 41%, and 28%, respectively. In the high-risk group (evidence of level IV/V metastases), the 5-year disease-free, disease-specific, and overall survival rates were 14%, 12%, and 10%, respectively. CONCLUSIONS Among OSCC patients with ECS, those with level IV/V metastases appear to have the worst prognosis followed by without level IV/V metastases and tumor depth ≥12 mm. An aggressive therapeutic approach may be suitable for intermediate- and high-risk patients.