Joseph Tung-Chieh Chang

Prospective Study of [18F]Fluorodeoxyglucose Positron Emission Tomography and Computed Tomography and Magnetic Resonance Imaging in Oral Cavity Squamous Cell Carcinoma With Palpably Negative Neck

PURPOSE To assess the clinical usefulness of [(18)F]fluorodeoxyglucose positron emission tomography ([18F]FDG PET) as well as computed tomography (CT) or magnetic resonance imaging (MRI) in oral squamous cell carcinoma (SCC) patients with palpably negative neck. PATIENTS AND METHODS In total, 134 oral SCC patients with palpably negative neck were prospectively evaluated with [18F]FDG PET, CT/MRI, and their visual correlation. Histopathologic analysis was used as the gold standard for assessment of these imaging techniques. RESULTS Thirty-five (26.1%) of our 134 patients were found to have neck metastases. On a level-by-level basis, the sensitivity of [18F]FDG PET for nodal metastases was two-fold higher than that of CT/MRI (41.2% v 21.6%, respectively; P = .021). Visual correlation of [(18)F]FDG PET and CT/MRI yielded slightly higher sensitivity and specificity than [18F]FDG PET alone (47.1% v 41.2%, P = .25; 98.0% v 96.8%, P = .125, respectively). On a patient-by-patient basis, the sensitivity of [18F]FDG PET for neck metastases was 51.4% and increased to 57.1% after visual correlation with CT/MRI. The probabilities of occult neck metastasis after using [(18)F]FDG PET were 6.7% in T1 tumors, 10.8% in T2 tumors, 13.3% in T3 tumors, and 25% in T4 tumors and decreased to 3.3% in T1 tumors and to 9.2% in T2 tumors after visual correlation with CT/MRI. CONCLUSION [(18)F]FDG PET was superior to CT/MRI for detecting palpably occult neck metastasis of oral SCC. Because [(18)F]FDG PET could reduce the probability of occult neck metastasis to less than 15% in T1 to T3 tumors, it should be indicated for evaluation of these subpopulations.

Head and neck cancer in the betel quid chewing area: Recent advances in molecular carcinogenesis

Head and neck cancer (HNC) is one of the 10 most frequent cancers worldwide, with an estimated over 500 000 new cases being diagnosed annually. The overall 5‐year survival rate in patients with HNC is one of the lowest among common malignant neoplasms and has not significantly changed during the last two decades. Oral cavity squamous cell carcinoma (OSCC) shares part of HNC and has been reported to be increasing in the betel quid chewing area in recent years. During 2006, OSCC has become the sixth most common type of cancer in Taiwan, and it is also the fourth most common type of cancer among men. It follows that this type of cancer wreaks a high social and personal cost. Environmental carcinogens such as betel quid chewing, tobacco smoking and alcohol drinking have been identified as major risk factors for head and neck cancer. There is growing interest in understanding the relationship between genetic susceptibility and the prevalent environmental carcinogens for HNC prevention. Within this review, we discuss the molecular and cellular aspects of HNC carcinogenesis in Taiwan, an endemic betel quid chewing area. Knowledge of molecular carcinogenesis of HNC may provide critical clues for diagnosis, prognosis, individualization of therapy and molecular therapeutics. (Cancer Sci 2008; 99: 1507–1514)

Nodal metastases of nasopharyngeal carcinoma: patterns of disease on MRI and FDG PET

The patterns of nodal spread of nasopharyngeal carcinoma (NPC) have an important influence on treatment planning, but have not yet been fully addressed. We prospectively used MRI and FDG PET to document the patterns of nodal spread in NPC. One hundred and one patients with newly diagnosed NPC were studied with MRI and FDG PET. On MRI, nodes were considered as metastatic according to criteria regarding size, the presence of nodal necrosis, and extracapsular spread. FDG PET images were interpreted visually, and nodes were considered metastatic if they showed prominent FDG uptake against the background. Nodal metastases were found in 89 of our 101 patients. Analysis of the distributions of nodal metastases in these 89 patients showed that retropharyngeal nodes were less frequently involved than cervical nodes (82.0% vs 95.5%). The vast majority of cervical nodal metastases were to the internal jugular chain, including nodes at levels II, III, and IV, with decreasing incidences of 95.5%, 60.7%, and 34.8%, respectively. Level V nodal involvement was found in 27% of patients. Supraclavicular fossa nodal metastases were not uncommon and occurred in 22.5% of patients. Skip metastases in the lower-level nodes or supraclavicular fossa nodes occurred in 7.9% of patients. Mediastinal and abdominal metastatic adenopathy was present in 4.5% and 3.4% of patients, respectively, and was associated with advanced nodal metastasis in the supraclavicular fossa. Level VI (2.2%), level VII (1.1%), submandibular (2.2%), and parotid (3.4%) nodal metastases were uncommon and were always associated with advanced ipsilateral nodal metastases of the neck. We conclude that the combined use of FDG PET and MRI can comprehensively depict the pattern of nodal metastasis in NPC patients. Nodal metastases principally affected level II nodes, from which lymphatic spread extended down in an orderly manner to involve level III, level IV, and the supraclavicular fossa nodes, or extended posteriorly to involve level V nodes. The frequency of skip metastases was 7.9%. Distant spread to mediastinal or abdominal nodes was found in 3–5% of patients, usually in association with supraclavicular nodal metastases.

Locally recurrent nasopharyngeal carcinoma.

PURPOSE To assess the outcome of and determine prognostic factors for locally recurrent nasopharyngeal carcinoma (NPC) in patients treated with a second course of radiotherapy (RT). MATERIALS AND METHODS From 1982 to 1995, 186 NPC patients, who had initially been treated in the Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, developed local recurrence in the nasopharynx and were re-treated with RT (>/=20 Gy). The time from the initial RT to re-treatment ranged from 8 to 136 months (median: 23 months). All patients were treated with external RT and conformal radiotherapy was used in 35 patients after 1993. Fifteen received radiosurgery as a boost treatment. The RT dose at the nasopharyngeal tumor area ranged from 20 to 67.2 Gy (median 50 Gy). Eighty-two patients received one to eight courses of cisplatin-based chemotherapy in addition to RT. RESULTS The 1-, 3- and 5-year survival was 54.9, 22. 1 and 12.4%, respectively. Patients whose tumor relapsed later than 2 years after the first treatment had a better survival than those with earlier relapse (3-year survival: 30.1 vs. 10.8%; P=0.015), but the difference became insignificant in patients who received >/=50 Gy. Patients without evidence of intracranial invasion or cranial nerve palsy had better survival than those with such lesions (3-year survival: 30.9 vs. 3.7%; P=0.006). A re-treatment dose >/=50 Gy yielded better survival (3-year survival: 22.8 vs. 18.5%; P=0.003). Addition use of radiosurgery may improve survival. The use of chemotherapy did not improve survival. Conformal radiotherapy resulted in significantly fewer severe complications than conventional RT. CONCLUSIONS A repeat course of RT for locally recurrent NPC successfully prolongs survival in a significant number of patients. Intracranial invasion and/or cranial nerve palsy and re-treatment dose affect the prognosis, with a dose of >/=50 Gy significantly improving survival. Radiosurgery boost may also improve survival. Our preliminary data indicates that conformal radiotherapy may decrease the severity of radiation-induced complications. However; longer follow-up and larger sample size is necessary to document the findings.

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.

Randomized Trial of Neoadjuvant Cisplatin, Vincristine, Bleomycin, and Radical Hysterectomy Versus Radiation Therapy for Bulky Stage IB and IIA Cervical Cancer

PURPOSE To compare the efficacy of neoadjuvant chemotherapy (NAC) followed by radical hysterectomy with that of radiotherapy (R/T) for bulky early-stage cervical cancer. PATIENTS AND METHODS Women with previously untreated bulky (primary tumor >/= 4 cm) stage IB or IIA non-small-cell carcinoma of the uterine cervix were randomly assigned to receive either cisplatin 50 mg/m(2) and vincristine 1 mg/m(2) for 1 day and bleomycin 25 mg/m(2) for 3 days for three cycles followed by radical hysterectomy (NAC arm) or receive primary pelvic radiotherapy only (R/T arm). The ratio of patient allocation was 6:4 for the NAC and R/T arms. Women with enlarged para-aortic lymph nodes on image study were ineligible unless results of cytologic or histologic studies were negative. RESULTS Of the 124 eligible patients, 68 in the NAC arm and 52 in the R/T arm could be evaluated. The median duration of follow-up was 39 months. Thirty-one percent of patients in the NAC arm and 27% in the R/T arm had relapse or persistent diseases after treatment, and 21% in each group died of disease. Estimated cumulative survival rates at 2 years were 81% for the NAC arm and 84% for the R/T arm; the 5-year rates were 70% and 61%, respectively. There were no significant differences in disease-free survival and overall survival. CONCLUSION NAC followed by radical hysterectomy and primary R/T showed similar efficacy for bulky stage IB or IIA cervical cancer. Further study to identify patient subgroups better suited for either treatment modality and to evaluate the concurrent use of cisplatin and radiation without routine hysterectomy is necessary.

The prognostic significance of pre- and posttreatment SCC levels in patients with squamous cell carcinoma of the cervix treated by radiotherapy

PURPOSE To investigate the prognostic significance of the pre- and posttreatment serum squamous cell carcinoma antigen (SCC) levels in patients with Stage I-IVA squamous cell carcinoma of the cervix primarily treated by radiotherapy. MATERIALS AND METHODS 401 patients with squamous cell carcinoma of cervix primarily treated with radiotherapy (RT) were included in this study. All had preRT, and 249 patients had postRT serum SCC values. The association of pretreatment SCC level with the clinical parameters, including stage, hemoglobin (Hb) level, age, cell differentiation, and lymph node status, was assessed by univariate and multivariate analysis. The prognostic significance of pretreatment SCC level and these clinical parameters were evaluated. The impact of postRT residual induration and SCC levels on survival was analyzed. RESULTS 1. PreRT SCC level strongly correlated with stage. After controlling for stage, only SCC levels higher than 10 ng/ml were associated with enlarged lymph nodes shown in CT scan. No association of preRT SCC level with other clinical parameters was found. 2. SCC level higher than 10 ng/ml, but not between 2-10 ng/ml, had significant impact on survival in a multivariate analysis. Stage, Hb levels (<10 g/dl) and positive lymph node shown by CT scan were also independent prognostic factors for survival. No significant difference in failure pattern in terms of local and/or distant sites was found in patients with different SCC levels. 3. Patients with residual induration and/or persistently elevated SCC level at 2-3 months after RT had a significantly higher incidence of treatment failure. Persistently elevated SCC level is a stronger predictor for treatment failure than residual induration by pelvic examination, and is associated with a higher incidence of distant metastasis. One third of patients with initial SCC level higher than 10 ng/ml had persistently elevated SCC. CONCLUSION Pretreatment SCC levels higher than 10 ng/ml are an independent predictor for poor prognosis in patients included in this study, and can be used as one of the prognostic factors for selection of patients for intensive treatment. Persistently elevated SCC levels after RT is a strong predictor for treatment failure. A combination of clinical pelvic examination and SCC levels provides useful information for the need of further work-up and management.

The role of brachytherapy in early-stage nasopharyngeal carcinoma

PURPOSE To present the treatment results and assess the optimal radiation dose and the role of brachytherapy in early stage nasopharyngeal cancer (NPC). METHODS AND MATERIALS One hundred eighty-three patients with Stage I and II (American Joint Committee on Cancer Staging System, 1987) NPC completed the planned radiotherapy in our institution from 1979 to 1991. In 133 patients, radiotherapy was given to the nasopharynx by external beam to 64.8-68.4 Gy. Further boost was done by high dose rate (HDR) brachytherapy for 5-16.5 Gy in one to three fractions. For the remaining 50 patients, a course of external radiotherapy to the nasopharynx for 68.4-72 Gy was given to nasopharynx. Age (>40 or not), sex, neck boost or not, brachytherapy, and irradiation dose were analyzed to determine significant factors that influence the probabilities of local control and actuarial survival. RESULTS The 5-year disease-specific survival was 85.8% and local control was 83%. Only the brachytherapy and irradiation dose significantly affected the results. The use of the brachytherapy had significant impact on overall survival and local control. Furthermore, we compared the prognostic effect of various radiation dosage among Group I of 50 patients (<72.5 Gy, no brachytherapy, excluding four patients who received brachytherapy), Group II of 71 patients (72.5-75 Gy; one to two fractions of brachytherapy), and Group III of 58 patients (>75 Gy; three fractions of brachytherapy). Five-year disease-specific survival rates of Group I, Group II, and Group III were 77, 95.5, and 82.4%, respectively. Five-year local control rates were: 73.7, 93.9, and 79.5%. We found that the Group II had the best actuarial survival and local control rate (log-rank test,p < 0.05). Most patients receiving brachytherapy encountered foul odor because of nasopharynx crust; 12 of them had palate or sphenoid sinus floor perforation or nasopharynx necrosis. None of the patients without brachytherapy experienced the same complications. CONCLUSIONS The optimal radiotherapy dose to the nasopharynx area in early stage NPC may be within 72.5 to 75 Gy by our treatment protocol. A dose of more than 75 Gy did not have significant local control or survival advantage. The use of brachytherapy to elevate radiation dose had significant local control and survival benefit for early stage NPC patients, but the fractionation size should be decreased to reduce the complications.

Oncogenic function and early detection potential of miRNA-10b in oral cancer as identified by microRNA profiling

The miRNA participates in a variety of biologic processes, and dysregulation of miRNA is associated with malignant transformation. In this study, we determined specific profile of miRNA associated with oral cancer by using miRNA array screening method. There were 23 miRNAs found with considerably differential expressions between six oral cancer cell lines and five lines of normal oral keratinocytes, in which, 10 miRNAs showed the highest significant difference after independent examination by reverse transcription quantitative PCR. Eight molecules were upregulated, miR-10b, miR-196a, miR-196b, miR-582-5p, miR-15b, miR-301, miR-148b, and miR-128a, and two molecules, miR-503 and miR-31, were downregulated. The most upregulated miR-10b was further examined, and its functions were characterized in two oral cancer cell lines. The miR-10b actively promotes cell migration (2.6- to 3.6-fold) and invasion (1.7- to 1.9-fold) but has minimal effect on cell growth or chemo-/radiosensitivity. Furthermore, miR-10b was considerably elevated in the plasma of xenografted tumor mice (20-fold). This upregulation of miR-10b in plasma was further shown in the patients with oral cancer [P < 0.0001, area under curve (AUC) = 0.932] and precancer lesions (P < 0.0001, AUC = 0.967), suggesting that miR-10b possesses a high potential to discriminate the normal subjects. In conclusion, we have identified at least 10 miRNAs significantly associated with oral cancer, including the most elevated miR-10b. The miR-10b actively participates in cancer formation by promoting cell migration and invasion. Our study using clinical samples suggests that plasma miR-10b has high potential as an early detection marker for oral cancer. Cancer Prev Res; 5(4); 665–74. ©2012 AACR.

Analysis of risk factors for distant metastases in squamous cell carcinoma of the oral cavity

The number of patients with oral cavity squamous cell carcinoma (OSCC) is increasing. Because the characteristics of patients with OSCC who develop distant metastases (DM) remain uncertain, the authors analyzed potential risk factors.