Adjuvant chemotherapy with S-1 after curative chemoradiotherapy in patients with locoregionally advanced squamous cell carcinoma of the head and neck: Reanalysis of the ACTS-HNC study.

BACKGROUND: Chemoradiotherapy (CRT) has improved organ preservation or overall survival (OS) of locoregionally advanced head and neck squamous cell cancer (LAHNSCC), but in clinical trials of conventional CRT, increasing CRT intensity has not been shown to improve OS. In the Adjuvant ChemoTherapy with S-1 after curative treatment in patients with Head and Neck Cancer (ACTS-HNC) phase III study, OS of curative locoregional treatments improved more with adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) than with tegafur/uracil (UFT). ACTS HNC study showed the significant efficacy of S-1 after curative radiotherapy in sub-analysis. We explored the efficacy of S-1 after curative CRT in a subset of patients from the ACTS-HNC study. METHODS: Patients with stage III, IVA, or IVB LAHNSCC were enrolled in this study to evaluate the efficacy of S-1 compared with UFT as adjuvant chemotherapy after curative CRT in the ACTS-HNC study. Patients received S-1 at 80-120 mg/day in two divided doses for 2 weeks, followed by a 1-week rest, or UFT 300 or 400 mg/day in two or three divided doses daily, for 1 year. The endpoints were OS, disease-free survival, locoregional relapse-free survival, distant metastasis-free survival (DMFS), and post-locoregional relapse survival. RESULTS: One hundred eighty patients (S-1, n = 87; UFT, n = 93) were included in this study. Clinical characteristics of the S-1 and UFT arms were similar. S-1 after CRT significantly improved OS (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.22-0.93) and DMFS (HR, 0.50; 95% CI, 0.26-0.97) compared with UFT. CONCLUSION: As adjuvant chemotherapy, S-1 demonstrated better efficacy for OS and DMFS than UFT in patients with LAHNSCC after curative CRT and may be considered a treatment option following curative CRT. For this study was not preplanned in the ACTS-HNC study, the results is hypothesis generating but not definitive.

Randomized phase III trial of adjuvant chemotherapy with S-1 after curative treatment in patients with squamous-cell carcinoma of the head and neck (ACTS-HNC).

BACKGROUND: We conducted a phase III study to evaluate S-1 as compared with UFT as control in patients after curative therapy for stage III, IVA, or IVB squamous-cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Patients were randomly assigned to the UFT group (300 or 400 mg day-1 for 1 year) or the S-1 group (80, 100, or 120 mg day-1 for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were relapse-free survival, overall survival (OS), and safety. RESULTS: A total of 526 patients were enrolled, and 505 were eligible for analysis. The 3-year DFS rate was 60.0% in the UFT group and 64.1% in the S-1 group (HR, 0.87; 95%CI, 0.66-1.16; p = 0.34). The 3-year OS rate was 75.8% and 82.9%, respectively (HR, 0.64; 95% CI, 0.44-0.94; p = 0.022). Among grade 3 or higher adverse events, the incidences of leukopenia (5.2%), neutropenia (3.6%), thrombocytopenia (2.0%), and mucositis/stomatitis (2.4%) were significantly higher in the S-1 group. CONCLUSIONS: Although DFS did not differ significantly between the groups, OS was significantly better in the S-1 group than in the UFT group. S-1 is considered a treatment option after curative therapy for stage III, IVA, IVB SCCHN. TRIAL REGISTRATION: ClinicalTrials.gov NCT00336947 http://clinicaltrials.gov/show/NCT00336947.

[Clinical analysis of mandibular osteoradionecrosis].

Radiotherapy thought vital in treating head and neck cancer, occasionally causes seriously local complications such as mandibular osteoradionecrosis (ORN). An analysis of mandibular ORN cases showed 16 in 638 subjects treated by radiotherapy, for an ORN rate of 2.5%. This rate was highest in subjects with oral cancer excluding the tongue, administered 81 Gy radiation dose, using X-ray plus electronic beams. 8 cases of ORN occurred within 1 year following radiation, and the 8 others within 5 years. Preservation treatment was successful in 44% of ORN cases, including surgery, for which the rate of final cure was 63%. With case of cancer recurrence, the rate was 25%. In 2 subjects dying of aspiration pneumonia, the cause should be a particular point for reflection. Radiotherapy involving mandibular bone should include special consideration related to the radiation source, radiation dose. Once ORN occurred, we should take care of the mixed cancer and dysphagia in the treatment.

[A clinical study of nonsquamous cell carcinoma of the nasal and paranasal sinuses].

We evaluated the efficacy of multimodality therapy for nonsquamous cell carcinoma (salivary carcinoma) of the nasal and paranasal sinuses. We retrospectively analyzed 28 patients with nonsquamous cell carcinoma of the nasal cavity and paranasal sinuses between 1972 and 2005. Primary sites were the maxillary sinus in 20 patients, ethmoidal sinus in 1, and the nasal cavity in 7. Pathology included adenocarcinoma in 5, mucoepidermoid carcinoma in 4, adenoid cystic carcinoma in 18, and adenosquamous carcinoma in 1. Five-year survival was 55% in all cases, 50% in the maxillary and ethmoidal sinuses, and 71% in the nasal cavity. Adenoid cystic carcinoma recurrence persisted over the five years following primary treatment and salvage after recurrence was 0%. Multimodality therapy decreased primary-site recurrence more than nonmultimodality therapy. Multimodality therapy thus appears useful in the primary treatment of nonsquamous cell carcinoma in the nasal cavity and paranasal sinuses.

The role of dihydropyrimidine dehydrogenase expression in resistance to 5-fluorouracil in head and neck squamous cell carcinoma cells.

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs to treat cancer patients. However, the presence of drug resistant tumor cells may cause a poor response to 5-FU based chemotherapy. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in the degradation of pyrimidine bases and is also responsible for the degradation of 5-FU. In this study, we examined whether DPD expression affects the cytotoxic activity of 5-FU against head and neck squamous cell carcinoma (HNSCC) and the role of DPD in the biological regulation of HNSCC. We constitutively expressed the DPD cDNA in a HNSCC cell line. The effect of DPD expression on in vitro cell growth, cell cycle and 5-FU cytotoxicity was examined. In addition, we also evaluated the association between DPD expression and the proliferation of tumor cells in surgical specimens, and prognosis of the patients with HNSCC. DPD overexpression decreases the cytotoxicity of 5-FU. CDHP, a strong DPD inhibitor, enhances the cytotoxic effect of 5-FU in HNSCC cells in vitro. DPD expression level does not effect cell proliferation and does not seem to have prognostic value in HNSCC. The present results strongly indicate that DPD expression plays an important role in the sensitivity of HNSCC to 5-FU chemotherapy, suggesting the possibility of personalized chemotherapy including the prediction of response and adverse effects.

[The present situation of neoadjuvant therapy for head and neck carcinoma].

Cisplatin and infusional 5-fluorouracil were most commonly used as neoadjuvant chemotherapy or induction chemotherapy for squamous cell carcinoma of head and neck (SCCHN). But current analysis of neoadjuvant chemotherapy trials in head and neck cancer have not demonstrated a survival benefit for the use of induction therapy. Taxanes are an effective anti-cancer drug for SCCHN. New regimens including Taxanes as neoadjuvant chemotherapy for SCCHN are recommended.

Efficacy of intra-arterial infusion chemotherapy for head and neck cancers using coaxial catheter technique: initial experience.

The aim of this study was to evaluate the efficacy of intra-arterial infusion chemotherapy for head and neck cancers using a coaxial catheter technique: the superficial temporal artery (STA)-coaxial catheter method. Thirty-one patients (21 males and 10 females; 37-83 years of age) with squamous cell carcinoma of the head and neck (maxilla, 2; epipharynx, 4; mesopharynx, 8; oral floor, 4; tongue, 10; lower gingiva, 1; buccal mucosa, 2) were treated by intra-arterial infusion chemotherapy. Four patients were excluded from the tumor-response evaluation because of a previous operation or impossibility of treatment due to catheter trouble. Forty-eight sessions of catheterization were performed. A guiding catheter was inserted into the STA and a microcatheter was advanced into the tumor-feeding artery via the guiding catheter under angiographic guidance. When the location of the tumor or its feeding artery was uncertain on angiography, computed tomographic angiography was performed. The anticancer agent carboplatin (CBDCA) was continuously injected for 24 h through the microcatheter from a portable infusion pump attached to the patient's waist. The total administration dose was 300-1300 mg per body. External radiotherapy was administered during intra-arterial chemotherapy at a total dose of 21-70.5 Gy. The initial response was complete response in 15 patients, partial response in 7 patients, and no change in 5 patients; the overall response rate was 81.5% (22/27). Complication-related catheter maintenance was observed in 15 of 48 sessions of catheterization. Injury and dislocation of the microcatheter occurred 10 times in 7 patients. Catheter infection was observed three times in each of two patients, and catheter occlusion and vasculitis occurred in two patients. Intra-arterial infusion chemotherapy via the STA-coaxial catheter method could have potential as a favorable treatment for head and neck tumors.

Clinical value of serum squamous cell carcinoma antigen in the management of sinonasal inverted papilloma.

BACKGROUND: Although sinonasal inverted papilloma (IP) is a rare benign tumor, it has a tendency to recur and is sometimes associated with squamous cell carcinoma (SCC). Therefore, postoperative long-term follow-up of these patients is recommended. We previously reported that serum SCC antigen might be a useful tumor marker for sinonasal IP. In this study, we investigated whether serum SCC antigen level has a correlation with disease status and is useful in the early detection of recurrent disease. METHODS: Blood samples for the analysis of serum SCC antigen were taken from 28 IP patients before and after surgical treatment. RESULTS: Twenty-five (89%) of 28 cases showed evaluated serum SCC antigen levels above the upper limit. This marker level decreased in all cases after surgical resection. Four of these patients had a recurrence. None of the patients with recurrent tumor showed symptoms at the time of detection of their recurrent tumor, and recurrence was discovered from elevated levels of SCC antigen. CONCLUSIONS: Serum SCC antigen level has a correlation with disease status of IP and has a potential to serve as a useful tool for monitoring the course of disease. SCC antigen is a reliable tumor marker in the management of sinonasal IPs.

Traumatic neuroma and recurrent lymphadenopathy after neck dissection: comparison of radiologic features.

PURPOSE: To retrospectively evaluate the ultrasonographic (US), computed tomographic (CT), and magnetic resonance (MR) imaging features that differentiate traumatic neuroma from recurrent lymphadenopathy after neck dissection. MATERIALS AND METHODS: Imaging findings of 10 patients with a traumatic neuroma and 17 with recurrent lymphadenopathy were reviewed. US and CT were performed in all patients; MR imaging was performed in 16 patients. Findings analyzed at US included the diameter of the long and short axes, the short-axis-to-long-axis ratio, and the presence of a central hyperechoic area. Findings analyzed at CT were contiguity with common or internal carotid artery, lesion location in correlation with carotid artery, and the presence of a hyperattenuating rim. Findings analyzed at MR imaging included signal intensity on T1- and T2-weighted images, the presence of ring enhancement, and the presence of a hypointense rim on T2-weighted images. RESULTS: Statistically significant differences were found between traumatic neuroma and recurrent lymphadenopathy in the short-axis-to-long-axis ratio (mean, 0.47 vs 0.72; P < .001), the short-axis diameter (mean, 5.7 vs 12.2 mm; P < .001), the presence of a central hyperechoic area (five of 10 patients [50%] vs one of 17 patients [6%]; P < .05), the frequency of contact with carotid artery (two of 10 patients [20%] vs 13 of 17 patients [76%]; P < .01), and the presence of a hypointense rim on T2-weighted MR images (three of six patients [50%] vs zero of 10 patients [0%]; P < .05). Findings in other parameters were not statistically significant. CONCLUSION: Several imaging findings can differentiate traumatic neuroma from recurrent lymphadenopathy after neck dissection.

H-ras mutation is an additional event of sarcomatous transformation in aerodigestive spindle cell carcinoma.

The conversion from a carcinomatous component to a sarcomatous one in spindle cell carcinoma (SPCC) of the upper aerodigestive tract is thought to occur via a series of molecular alterations; however the detailed mechanism is still unknown. We examined mutations at the H-ras and p53 genes in 16 SPCCs of upper aerodigestive tracts using PCR-RFLP, PCR-SSCP and direct sequencing analysis. The two distinct components, sarcomatous and carcinomatous components in SPCC, were analyzed independently. p53 mutations were detected in both components of SPCC (50.0%, 8/16), and those in the sarcomatous component were completely in accordance with those in the carcinomatous one. In contrast, H-ras mutations were detected only in the sarcomatous component (12.5%, 2/16), and not in the carcinomatous one (0%, 0/16). There was a statistically significant difference in prognosis between the patients with the H-ras mutation (n=2) and those without (n=14); the former had poorer prognosis (P=0.0049). Our results seem to suggest that the H-ras mutation is a relatively uncommon event in SPCC; however, the presence of H-ras mutations may be associated with a more malignant potential in SPCC, while actually occurring during the sarcomatous change itself.

Efficacy of intra-arterial infusion therapy using a combination of cisplatin and docetaxel for recurrent head and neck cancers compared with cisplatin alone.

AIMS: To compare the initial effect and toxicity, response duration and survival time of intra-arterial infusion therapy using a combination of cisplatin (CDDP) and docetaxel (DXT) with those using CDDP alone for treatment of recurrent head and neck cancers. MATERIALS AND METHODS: Twenty-nine patients with recurrent head and neck cancers were treated using intra-arterial infusion chemotherapy. The chemotherapeutic regimens consisted of CDDP alone (n=12) or a combination of CDDP and DTX (n=17). In the CDDP-DTX group, both CDDP 70 mg/m2 and DTX 60 mg/m2 were administrated via the external carotid artery (ECA) or via branches of the ECA or subclavian artery. In the CDDP-alone group, CDDP 70 mg/m2 was infused. The tumour response (response rate = complete response + partial response) and toxicities (World Health Organization [WHO] classification grades 3 and 4) were evaluated in both groups and compared by Fisher's exact probability test. RESULTS: The response rates in the CDDP-DTX group and the CDDP-alone group were 71% (12/17) and 50% (6/12), respectively (P=0.44). Leucocytopenia and neutropenia (grades 3 and 4) were significantly more prevalent in the former than in the latter group (11/17 vs 1/12; 10/17 vs 1/12) (P<0.01). However, there were no infectious diseases in any of the patients. CONCLUSION: Combined cisplatin-docetaxel intra-arterial infusion therapy was shown to be effective and safe for recurrent head and neck cancers.

Salivary gland tumors: diagnostic value of gadolinium-enhanced dynamic MR imaging with histopathologic correlation.

PURPOSE: To evaluate the diagnostic value of gadolinium-enhanced dynamic magnetic resonance (MR) imaging of salivary gland tumors and correlate the MR imaging and histopathologic findings. MATERIALS AND METHODS: Thirty-three salivary gland tumors in 29 patients were examined preoperatively at gadolinium-enhanced dynamic MR imaging. There were 22 benign and 11 malignant tumors. Dynamic contrast material-enhanced MR images were obtained for 5 minutes. Time of peak enhancement (T(peak)) and washout ratio (WR) were determined from time-signal intensity curves (TICs). Microvessel count and cellularity-stromal grade were evaluated histopathologically. The strengths of correlations between T(peak) and microvessel count and between WR and cellularity-stromal grade were statistically analyzed. Statistical analysis was also performed to determine whether any differences among the various histopathologic tumor types existed [corrected]. In a validation study, 13 salivary gland tumors in 13 patients were examined consecutively. RESULTS: At a T(peak) of 120 seconds, malignant tumors could be differentiated from pleomorphic adenomas but not from Warthin tumors. A WR of 30%, however, enabled differentiation between malignant and Warthin tumors. Classification of TICs on the basis of a T(peak) of 120 seconds and a WR of 30% had high sensitivity (91%) and specificity (91%) in the differentiation of benign and malignant tumors. Correlations between T(peak) and microvessel count (P <.0001, rho = -0.800) and between WR and cellularity-stromal grade (P =.0105, rho = 0.572) were significant. The validation study also yielded high sensitivity (100%) and specificity (80%) in the differentiation between benign and malignant tumors. CONCLUSION: Gadolinium-enhanced dynamic MR imaging is useful for differentiating benign from malignant salivary gland tumors.

Constitutive activation of signal transducers and activators of transcription 3 correlates with cyclin D1 overexpression and may provide a novel prognostic marker in head and neck squamous cell carcinoma.

The precise mechanism responsible for the frequent overexpression of cyclinD1 in human head and neck squamous cell carcinoma (HNSCC) is not known. In view of the fact that signal transducers and activators of transcription 3 (Stat3) is often activated in HNSCC cells, we examined the effects of Stat3 on cyclin D1 expression and cell proliferation in the YCU-H891 HNSCC cell line that displays constitutive activation of Stat3. Expression of a dominant negative Stat3 construct in YCU-H891 cells inhibited proliferation, cyclin D1 promoter activity, and cellular levels of cyclin D1 mRNA and protein. The levels of the antiapoptotic Bcl-2 and Bcl-X(L) proteins were also inhibited. In 51 primary tumor samples from patients with squamous cell carcinoma of the p.o. tongue, there was a significant correlation between increased levels of the activated form of Stat3, phosphorylated-Stat3, and increased levels of cyclin D1 (P < 0.0001). Increased tumor levels of phosphorylated-Stat3 were also associated with lower survival rates (P < 0.01). This study provides the first evidence that in HNSCC, constitutive activation of Stat3 plays a causative role in overexpression of cyclin D1, and in clinical studies, Stat3 activation may provide a novel prognostic factor. Furthermore, agents that target Stat3 may be useful in the treatment of HNSCC.

CT and MR features of nasopharyngeal carcinoma in children and young adults.

AIM: To clarify CT and MR features of nasopharyngeal carcinoma (NPC) in children and young adults. METHOD: CT and MR findings of 13 patients (30 years old or younger) with a histopathologic diagnosis of NPC were reviewed. RESULTS: Skull base invasion (12/13), lymphadenopathy (10/13), and infiltrative growth (8/8) were common findings. The signal intensity of tumours was slightly higher than that of muscles in six cases and isointense to that of muscles in two cases on T1-weighted images; it was higher than that of muscle and lower than that of cerebellar grey matter on T2-weighted images in all cases. Internal signals were homogeneous in both pre- and post-Gd-enhanced MR images in all cases. CONCLUSIONS: Despite its rarity in this age group, NPC should be included in a differential diagnosis when CT and MR imaging reveal these features.

Serum squamous cell carcinoma antigen is a useful biologic marker in patients with inverted papillomas of the sinonasal tract.

BACKGROUND: Inverted papilloma (IP) is a frequent benign sinonasal tumor that is characterized histologically by squamous metaplasia, epithelial acanthosis, and hyperplasia of the nasal epithelium. Because of its high recurrence rate and malignant transformation potential, careful long-term follow up is necessary. METHODS: The purpose of the current report was to study the expression of squamous cell carcinoma (SCC) antigen in sinonasal IPs and to evaluate the usefulness of SCC antigen as a biologic marker for the follow-up of patients with sinonasal IP. The expression of SCCA1 in three sinonasal IP cases, three sinonasal SCC cases, and cases of normal nasal epithelium were examined by Western blot analysis, and the SCCA1 expression pattern in 31 IP specimens and 4 carcinoma in IP specimens were evaluated immunohistochemically. The serum levels of SCC antigen in 11 patients with sinonasal IP also were analyzed. RESULTS: SCCA1 was overexpressed in all three sinonasal IP tissues compared with sinonasal SCC tissues or normal nasal epithelium. SCCA1 cytoplasmic immunoreactivity was detected in the suprabasal epidermal keratinocytes of all 31 sinonasal IP cases. In the four carcinoma in IP specimens, SCCA1 expression in the papillomatous lesion was more intense than in the cancerous lesion. The serum SCC antigen level was high in 10 of 11 patients with IP (91%) and significantly decreased after surgical resection of the tumors. CONCLUSIONS: The results of the current study indicate that SCCA1 frequently is overexpressed and may play a biologic role in the development of sinonasal IPs. Serum SCC antigen may be a useful biologic marker in patients with sinonasal IP.