Antiemetic effects of granisetron and dexamethasone combination therapy during cisplatin-containing chemotherapy for head and neck cancer: dexamethasone dosage verification trial.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) remains a significant problem for patients and is associated with a substantial deterioration in quality of life; appropriate use of antiemetic drugs is crucial in maintaining the quality of life in patients undergoing chemotherapy. METHODS: This randomized, crossover trial evaluated the antiemetic efficacy and safety of 8 mg per day (low-dose) and 16 mg per day (standard-dose) dexamethasone, in combination with the 5-HT(3) receptor antagonist granisetron, in 36 patients receiving cisplatin (CDDP)-containing chemotherapy for head and neck cancer. Following chemotherapy, the antinausea/vomiting inhibition rate for each dexamethasone dose was measured. RESULTS: During the 24-h period following administration of chemotherapy (acute phase), the antinausea/vomiting inhibition rates (no nausea and no episodes of vomiting) for 8 mg and 16 mg dexamethasone were comparably high (58.3% and 63.8%, respectively; P = 0.8092). Similar results were seen on days 2-5 following chemotherapy. Efficacy during the acute phase, based on the number of instances of vomiting and degree of nausea, was also comparably high for the two dexamethasone doses (overall efficacy rates were 94.4% and 88.8%, respectively, for 8 mg and 16 mg dexamethasone; P = 0.7637). Both doses maintained an 80% or higher response rate until day 3, and neither dose produced severe side effects. CONCLUSION: The results suggest that granisetron and dexamethasone combination therapy is useful in controlling acute and delayed nausea and vomiting induced by CDDP-containing chemotherapy for head and neck cancer. Furthermore, 8 mg and 16 mg dexamethasone have equivalent antiemetic efficacy.

Efficacy of concurrent chemoradiotherapy for T1 and T2 laryngeal squamous cell carcinoma regarding organ preservation.

BACKGROUND: Although the survival rate of early-stage laryngeal squamous cell carcinoma (SCC) patients treated by radiotherapy (RT) is sufficient, the larynx preservation rate is unsatisfactory. To improve the larynx preservation rate, such patients have been treated by RT with chemotherapeutic agents. PATIENTS AND METHODS: RT with or without uracil-tegafur (UFT) was performed for T1 cases, and UFT and carboplatin for T2 cases. RESULTS: In T1 cases, 30 patients received RT and 16 patients received concurrent chemoradiotherapy (CCRT). In T2 cases, 28 patients received RT and 45 patients received CCRT. There were no significant differences in the response and survival rates between the treatment methods both in T1 and T2 cases. The 5-year larynx preservation survival rate was improved significantly by CCRT in T2 cases (66.7% vs. 93.3%; p < 0.01). CONCLUSION: CCRT for early-stage laryngeal SCC patients was efficacious to improve the larynx preservation survival rate.

Analysis of feasibility and toxicity of concurrent chemoradiotherapy with S-1 for locally advanced squamous cell carcinoma of the head and neck in elderly cases and/or cases with comorbidity.

PURPOSE: The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with S-1 in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in elderly cases and/or cases with comorbidity. METHODS: Fifty eligible patients with stage III (15 cases) or stage IV (35 cases) SCCHN were treated with CCRT. Thirteen cases had an advanced age of over 75 years and 37 cases had comorbidity. Definitive radiotherapy was delivered up to a total dose of 66-70.2 Gy. The patients received two courses of oral S-1 (40 or 50 mg twice a day [80 or 100 mg/day]) for 2 weeks followed by 1 week of rest while receiving CCRT. RESULTS: All the patients received the planned radiotherapy and at least one course of S-1. Grade 3 mucositis occurred in 20% of the patients (10/50). Grade 3 neutropenia occurred in 12% (6/50) and leukocytopenia occurred in 6% (3/50) of the cases. Pathologically, the complete response rates were 93% in stage III and 54% in stage IV. CONCLUSION: Concurrent chemoradiotherapy with S-1 is a safe, well-tolerated and effective regimen for locally advanced SCCHN in elderly cases and/or cases with comorbidity.

Soluble form of ephrinB2 inhibits xenograft growth of squamous cell carcinoma of the head and neck.

The ephB4-ephrinB2 system plays an important role in the interaction of tumor cells with endothelial cells (ECs). To assess the role of ephB4 in the in vivo growth of head and neck squamous cell carcinoma (HNSCC), we used ephrinB2-Fc, a fusion protein consisting of the extracellular domain of ephrin-B2 and the Fc portion of human IgG1, as the soluble ligand for ephB4. EphrinB2-Fc injection into HNSCC xenografted mice significantly suppressed xenograft growth, accompanied by a decrease in vessel cross-sectional area, but there was no change in vessel number. EphrinB2-Fc injection also induced the formation of mature blood vessels rich in alpha-smooth muscle actin positive pericytes in the xenograft tissue. In vitro assays revealed that ephrinB2-Fc inhibited the proliferation of human umbilical vein ECs (HUVECs) but not tumor cells. Furthermore, real-time quantitative RT-PCR showed that ephrinB2-Fc down-regulated matrix metalloproteinase-2 mRNA expression in HUVECs and vascular endothelial growth factor-A in tumor cells. These data suggest that treatment with ephrinB2-Fc, the soluble ligand of ephB4, inhibited the growth of HNSCC through vessel maturation/stabilization, preventing leakiness and endothelial sprout formation.

The efficacy and safety of concurrent chemoradiotherapy for maxillary sinus squamous cell carcinoma patients.

OBJECTIVE: Combined treatment modality, e.g., definitive surgery followed by radiotherapy (RT) and definitive RT with concurrent chemotherapy, has been applied for advanced maxillary sinus squamous cell carcinoma (MSSCC) patients to obtain a better survival with organ preservation in Japan. METHODS: The outcome of 40 patients with MSSCC between 1991 and 2007 in our institute was analyzed retrospectively. There were 36 males and 4 females, the average age being 59.5 years (ranging from 34 to 81 years). The median follow-up time was 66.1 months. All the patients had received a combined treatment consisting of definitive surgery, RT, and intra-arterial or systemic chemotherapy. The chemotherapeutic regimen was different depending on the performance status and/or complications of the patients. Since 1998, concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate and leucovorin regimen (CCRT-PFML) instead of neo-adjuvant chemotherapy has been applied. RESULTS: The overall 5-year survival rate was 59.2%, the 5-year disease-specific survival rate was 71.7%, and the 5-year organ preservation survival rate was 42.4%. In the group receiving CCRT-PFML, the overall 5-year survival rate was 60.0%, the 5-year disease-specific survival rate was 76.0%, and the 5-year organ preservation survival rate was 60.3%. CONCLUSION: CCRT-PFML for advanced MSSCC patients is feasible to preserve the organs without reducing the survival rate.

Treatment results and prognostic factors for advanced squamous cell carcinoma of the head and neck treated with concurrent chemoradiotherapy.

OBJECTIVE: To review our experience in the treatment of concurrent chemoradiotherapy (CCR) for patients with advanced squamous cell carcinoma of the head and neck (SCCHN) and to evaluate the different factors affecting survival and primary organ preservation. METHODS: We reviewed the records of 101 patients with SCCHN treated with CCR between February 1998 and April 2004. Of 101 patients, 76 were treated with a cisplatin, 5-fluorouracil, methotrexate, and leucovorin (PFML) regimen and 25 were treated with a carboplatin and uracil-tegafur (CBDCA-UFT) regimen. Overall survival (OS), disease-specific survival (DSS) and DSS with primary organ preservation were estimated using Kaplan-Meier methods. The log-rank test and Cox proportional hazards regression were employed to identify significant prognostic factors for OS, DSS, and DSS with primary organ preservation. RESULTS: The 5-year OS and DSS for all patients were 51.6 and 67.4%, respectively. On multivariate analysis, resectability of the tumor and degree of histological differentiation were significant predictors of survival for patients undergoing CCR; T stage and differentiation were significant prognostic factors for primary organ preservation. CONCLUSION: In the treatment of CCR for advanced SCCHN, the survival rate of the patients with resectable tumors was excellent and significantly greater compared with the patients with unresectable tumors. T1 to T3 disease in patients with advanced resectable SCCHN is a good predictor of organ preservation. CCR may improve not only primary organ preservation (local control) but also survival in patients with poorly differentiated tumors.

Early assessment of clinical response to concurrent chemoradiotherapy in head and neck carcinoma using fluoro-2-deoxy-d-glucose positron emission tomography.

OBJECTIVES: The aim of this study is to assess the utility of FDG-PET in the evaluation of therapeutic effects at 4 weeks after the completion of the concurrent chemoradiotherapy (CCR) in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-one patients with previously untreated HNSCC were retrospectively investigated about FDG-PET, CT, MRI and biopsies of the carcinoma before and 4 weeks after the treatment. RESULTS: The results of pathological examinations after CCR showed 6 residual cases and 25 ones with a pathologically complete response (pCR). The specificity of FDG-PET was 80%, although the sensitivity was limited to 67%. CONCLUSIONS: FDG-PET has a high specificity but limited sensitivity to discriminate residual cancer from fibrosis or scar at 4 weeks after CCR. FDG-PET at 4 weeks after CCR was too early to perform because of limited sensitivity.

Concurrent chemoradiotherapy for T4 patients with hypopharyngeal and laryngeal squamous cell carcinomas.

OBJECTIVES: Concurrent chemoradiotherapy (CCR) was given for the previously untreated T4 hypopharyngeal and laryngeal squamous cell carcinoma patients and the response and survival rates were evaluated. PATIENTS AND METHODS: A total of 23 patients, namely, 15 for hypopharynx and 8 for larynx were eligible. These patients were given cisplatin and 5-fluorouracil based chemotherapeutic regimens with conventional radiotherapy for a total dose of 66.6-70.2 Gy. RESULTS: Ten out of the 15 hypopharyngeal carcinoma patients and 4 out of the 8 laryngeal carcinoma patients showed a complete response at the primary sites. The 5-year disease-specific survival rate was 59.4% in all the patients, 51.9% in the hypopharyngeal carcinoma patients, and 71.0% in the laryngeal patients. Seven out of the 12 resectable hypopharyngeal carcinoma patients and 4 out of 8 laryngeal carcinoma patients were able to do without total laryngectomy. CONCLUSIONS: Based on these results, the survival rate in the hypopharyngeal and laryngeal T4 carcinoma patients treated by CCR seems to be satisfactory and the possibility of organ preservation for the advanced patients is indicated.

Prognostic value of retropharyngeal node involvement in CT-based lymph node-positive pharyngeal cancer following radiotherapy.

BACKGROUND: The objective of this study was to evaluate the impact of metastasis to the retropharyngeal nodes (RPN) in CT-based lymph node-positive head and neck patients by comparing other node levels. PATIENTS AND METHODS: A total of 175 CT-based lymph node-positive patients with carcinoma of the head and neck were managed with definitive radiation therapy. RPN involvement was identified only in pharyngeal cancer. One hundred and twenty-seven patients were investigated using CT and MRI following the guidelines on CT-based elective nodal delineation. Fifty-two patients received induction chemotherapy and 58 received concurrent chemoradiotherapy. RESULTS: RPN involvement and lymph node size were identified as having a significant effect on the disease-free survival (DFS) in univariate analysis. Concurrent chemotherapy and RPN involvement significantly affected DFS on multivariate analysis in all pharyngeal cancer patients and non-nasopharyngeal cancer (NNP) patients. RPN involvement, level IV involvement and concurrent chemotherapy also significantly affected locoregional control. CONCLUSION: Our study confirmed a poor outcome was associated with RPN involvement in patients with CT-based node-positive pharyngeal cancer and NNP patients definitively treated by radiotherapy.

Decrease of creatinine clearance rate with aging in patients with head and neck cancer in Japan.

BACKGROUND: We aimed to clarify the reason for the lower dosage of cis-platinum (CDDP) in patients with head and neck cancer in Japan compared with that in other countries, by evaluating renal function. METHODS: We studied 375 patients with head and neck cancer who had been hospitalized from January 1998 to October 2005, to evaluate and treat the disease. The creatinine clearance rate (Ccr) was calculated at least three times before beginning the treatments, and the average Ccr was estimated to evaluate the renal function. RESULTS: The Ccr decreased with aging, and the percentages of patients with Ccr lower than 65 ml/min per 1.73 m(2) were 27.1% of patients in their fifties, 36.8% in their sixties, 62.3% in their seventies, and 87.5% in their eighties. There was no correlation between renal function and the Japanese lifestyle (i.e., diet. water consumption). CONCLUSION: The renal function of Japanese decreases rapidly with aging, whereas that of Americans is maintained for longer periods. The poor renal function of Japanese is one of the causes of the need to reduce the dosage of or avoid the administration of CDDP in cancer patients.

Antitumor effects of Nafamostat mesilate on head and neck squamous cell carcinoma.

OBJECTIVE: Nafamostat mesilate (FUT-175), a synthetic serine protease inhibitor, has antitumor activities toward adenocarcinoma, e.g., colon cancer. However, its antitumor effects on other types of cancer have been less extensively studied. We investigated the biological activities of Nafamostat mesilate on cell proliferation, cell-invasive potential and growth factor production in head and neck squamous cell carcinoma (HNSCC). METHODS: Two human HNSCC cell lines established in our department, YCU-L891 and -H891, and a human vulvar squamous cell carcinoma cell line, A431, were examined for the effect of Nafamostat mesilate. The effects on cell growth were evaluated using the MTT assay. The effects on the relative expression levels of mRNA were measured by quantitative RT-PCR. Cytokine secretion was analyzed by enzyme-linked immunosorbent assay. RESULTS: Nafamostat mesilate inhibited the proliferation of two HNSCC cell lines, YCU-L891 and YCU-H891, and A431. In these cell lines, Nafamostat mesilate down-regulated both matrix metalloproteinase (MMP)-2 and -9. In addition, it reduced the productions of vascular endothelial growth factor (VEGF) and transforming growth factor beta1 (TGF-beta1) by the tumor cells. CONCLUSION: Our results suggest that Nafamostat mesilate has potential for use as a treatment against local growth, invasion and metastasis of squamous cell carcinoma.

[Clinical efficacy of administration with S-1 alone for head and neck carcinoma].

Most head and neck carcinomas are squamous cell carcinomas (HNSCCs). The combination of cisplatin with a continuous infusion of 5-fluorouracil (5-FU) has been a standard chemotherapy regimen for HNSCC. Based on basic and clinical studies, the critical plasma concentration of 5-FU is suspected to be about 0.1 microg/ml. The administration of the conventional dose of S-1 including dihydropyrimidine dehydrogenase (DPD), an metabolic inhibitor of 5-FU, results in exceeding the critical plasma concentration of 5-FU, and the long-term administration with high plasma concentration of 5-FU is considered to show clinical effectiveness in head and neck cancer. The results of early and late phase II studies on head and neck carcinoma were also described in the present paper.

[Adjuvant chemotherapy with S-1 for advanced head and neck carcinoma].

Most cases of head and neck squamous cell carcinoma (HNSCC) are in the advanced stages, resulting in a poor prognosis. To improve the poor outcome, adjuvant chemotherapy is indispensable for advanced cases with a high relapse risk after standard definitive treatments including surgery and/or radiotherapy. To define an adequate administration schedule in adjuvant chemotherapy with S-1, a controlled randomized study in multi-institutes was done. The results showed the 2-week administration followed by 1-week rest was superior to the 4-week administration followed by the 2-week rest in terms of safety and efficacy. In the present paper, some problems of adjuvant chemotherapy were discussed, and the protocol was described in terms of a multi-institutional controlled randomized comparison study of S-1 versus UFT in an adjuvant chemotherapy setting for locally advanced HNSCC.

Concurrent chemoradiotherapy with cisplatin, 5-fluorouracil, methotrexate, and leucovorin in patients with advanced resectable squamous cell carcinoma of the larynx and hypopharynx.

CONCLUSIONS: This regimen of concurrent chemoradiotherapy was safe and well tolerated. In terms of larynx preservation, the present regimen appears to be useful for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and hypopharynx. OBJECTIVES: To evaluate the efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced resectable SCC of the larynx and hypopharynx, and to demonstrate the feasibility of larynx preservation. PATIENTS AND METHODS: Forty-six eligible patients were treated. The chemotherapy regimen consisted of a combination of four drugs: cisplatin (60 mg/m(2), day 4), 5-fluorouracil (5-FU) (600 mg/m(2) given continuously for 120 h, days 1-5), methotrexate (MTX) (30 mg/m(2), day 1), and leucovorin (LV) (20 mg/m(2), days 1-5). Two cycles of this regimen were given every 4 weeks during radiotherapy. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8-2.0 Gray, to a total dose of 66.6-70.2 Gray. RESULTS: The 3-year disease-specific survival rates of patients with laryngeal or hypopharyngeal SCC were 81.3% and 78%, respectively. The 3-year disease-specific survival rates with larynx preservation of patients with laryngeal or hypopharyngeal SCC were 46.7% and 59%, respectively. The main toxicities were neutropenia, dermatitis, mucositis, and infection.

[Change of creatinine clearance rate in accordance with aging in Japanese patients with head and neck cancer].

Most of the head and neck tumors are squamous cell carcinomas (SCCs), which are relatively sensitive to chemotherapeutic agents. Cis-platinum (CDDP), 5-fluorouracil and taxanes are widely used worldwide for SCCs, and CDDP is the most common agent. Renal toxicity is a well-known adverse effect of CDDP, and adequate pre and post-hydration or combined administration of neutralizing agents is performed during CDDP injection. Before the CDDP administration, we have to evaluate renal function of the patients using creatinine clearance rate (Ccr). In Japan, CDDP at the dose of 60-70 mg/m(2)/day is administered in cases with over 65 ml/min/1.73 m(2) of Ccr, whereas in cases under 60 ml/min/1.73 m(2), we use other drugs, e.g., carboplatin, to prevent the renal dysfunction followed by chemotherapy. In other countries, the dose of CDDP is 70-100 mg/m(2)/day, and the discrepancy is based on the poor renal function of Japanese. We calculated Ccrs of 107 head and neck cancer patients since January, 2004 to August, 2005, and evaluated renal function before any treatment. Ccr was decreased in proportion to aging. At the age of fifties, 43.5% of the patients indicated lower Ccr than 65 ml/min/1.73 m(2): sixties, 45.7%; seventies, 50.0%; and eighties, 85.7%. In the United States, the average glomerular filtration rate of over 70 year-old healthy people is estimated as 75 ml/min/ 1.73 m(2), and it is considered sufficient kidney function for the administration of CDDP at the dose of 70-100 mg/ m(2)/day. The incident rate of end-stage renal disease is 1.3 times higher in the United States than in Japan. The incident rate of diabetes, which is the main cause of renal dysfunction, is almost the same in both countries. Though the reason is unclear, it is the fact that the renal function of Japanese decreases quickly in accordance with aging.

Fibromatous polyp of the hypopharynx.

We treated a patient with hypopharyngeal fibromatous polyp and speculated the mechanism of this disease. Fibromatous polyp, consisting of fibrous tissue hyperplasia with small vessels, fatty cells and inflammatory cells, is a clinically diagnostic name. Most of pharyngeal fibromatous polyps are arising from the palatine tonsil, and those from the pharyngeal epithelium are rare. The greater part of hypopharyngeal tumors is squamous cell carcinomas, and benign tumors are really uncommon. Fibromatous polyp is not thought to be a true tumor, but the symptoms are almost the same as tumorous diseases, e.g., discomfort in the throat, swallowing difficulty and respiratory distress. Complete resection is used as the treatment method. We operated on this patient under a laryngoscope and successfully resected the polyp. Five months after the operation, there is no sign of recurrence and the patient has no symptoms. This type of polyp is considered to enlarge gradually and it can cause asphyxia and/or dysphagia, so complete ablation should be performed as soon as possible.

Myxofibrosarcoma of the hypopharynx.

Myxofibrosarcoma is common in the extremities, but rare in the head and neck region. Hypopharyngeal myxofibrosarcoma has not been reported previously. We report the first case of a patient with myxofibrosarcoma of the hypopharynx. We examined this patient once a month after the operation, and there has been no local recurrence and no distant metastasis. Sarcomas are rare in the hypopharynx, but we have to bear in mind their possibility. Though a low-grade myxofibrosarcoma is a low-grade malignancy, complete resection should be done. We have to pay more attention planning the treatment for neoplastic diseases.

Maxillary sinus carcinoma: the only symptom was neck lymph node swelling.

OBJECTIVE: Since maxillary sinus is composed of bone structure, the main symptoms of maxillary sinus carcinoma are related to the anatomical feature and the destructive lesion of the bony wall, such as cheek pain and nasal obstruction. METHODS: We report a female case with undifferentiated carcinoma in the right maxillary sinus, only appearing cervical swelling which was revealed as lymph node metastasis. RESULTS: CT and MRI findings showed just maxillary sinusitis with minor bone destruction. However, fluorine 18-labelled deoxyglucose positron emission tomography (FDG-PET) was useful for the detection of the primary site. The patient received concomitant chemoradiotherapy, and showed a complete response both in the primary site and neck lymph nodes. She has no recurrence for 18 months after the primary therapy. CONCLUSION: The main symptoms of maxillary sinus carcinoma are related to the local progression, and known to have less cervical lymph node metastasis. However, like the present case, there is a rare case that has no symptom and organic features associated with the local mass. With the best use of advanced diagnostic technique, e.g., FDG-PET, we could diagnose and treat atypical maxillary sinus carcinoma patients.

[A randomized crossover study of ramosetron plus dexamethasone for the prevention of nausea and vomiting induced by chemotherapy including cisplatin-comparison of ramosetron combined with 8 mg and 12 mg of dexamethasone].

A randomized crossover study between 0.3 mg of ramosetron (RAM) combined with 8 mg of dexamethasone (DEX) and 0.3 mg of RAM combined with 12 mg of DEX was performed to investigate the prevention of nausea and vomiting due to chemotherapy including 60 mg/m2 or 70 mg/m2 of cisplatin (CDDP) in patients with advanced head and neck squamous cell carcinoma (HNSCC). Twenty-five patients the study consisted of who received chemotherapy with CDDP were enrolled in the present study between January 2001 and December 2002 at the Yokohama City University School of Medicine or Yokohama City University Medical Center. The antiemetic effectiveness in the group receiving 12 mg of DEX was not significantly superior to the group receiving 8 mg of DEX. It was suggested that the antiemetic therapy of RAM 0.3 mg plus DEX 8 mg was effective for the prevention of nausea and vomiting induced by CDDP in patients with advanced HNSCC.

[A case of head and neck squamous cell carcinoma suffering from acute renal failure after methotrexate administrator].

A 56-year-old man was hospitalized for evaluation of left neck tumor. The biopsy of neck lymph node showed a squamous cell carcinoma. Since no primary lesion was detected, the diagnosis was primary unknown neck lymph node metastasis. The first course of our chemotherapeutic regimen consisted of CDDP, 5-FU, MTX and LV. After MTX infusion, the level of serum creatinine increased. Based on laboratory data, we diagnosed acute renal failure caused by MTX and added the infusion of Ringer and LV. The serum creatinine level decreased to the level before chemotherapy. In the second course, chemotherapy with only CDDP and 5-FU was administered, and the level of serum creatinine did not increase. In the present case, suitable intravenous drip infusion of Ringer's injection prevented irreversible renal dysfunction. Since the laboratory data did not show dysfunction of uriniferous tubule and renal glomerulus, we considered allergic nephritis as a possibility.