The importance of preoperative swallowing therapy in subtotal laryngectomies.

OBJECTIVE: To examine the utility of swallowing therapy (ST) before and after surgery in patients undergoing subtotal laryngectomy. STUDY DESIGN AND SETTING: From 1990 to 2000, 43 patients underwent subtotal laryngectomy. Prior to 1997 patients received ST only after surgery, while from 1997 on, patients scheduled for subtotal laryngectomy also received some sessions of ST before surgery. RESULTS: The average time to swallowing resumption was 27.76 +/- 5.206 days for the 25 patients who received ST only after surgery, and 16.38 +/- 2.953 for those who underwent ST both before and after surgery. CONCLUSION: The difference between the two groups was significant on Student's t test (P < 0.001) and shows that preoperative rehabilitation is of significant help in the early resumption of normal deglutition. SIGNIFICANCE: The authors find that the duration of nasogastric tube feeding is reduced in subjects who underwent ST.

Association between hypermethylated tumor and paired surgical margins in head and neck squamous cell carcinomas.

PURPOSE: Surgical margin status is reported to be a relevant prognostic factor in head and neck squamous cell carcinoma (HNSCC), associated with a high risk of local recurrence. This study examines whether gene-promoter hypermethylation could be detected in HNSCC surgical margins with no histologic evidence of malignancy, and if so, whether it reflects epigenetic events of primary tumors. EXPERIMENTAL DESIGN: Promoter methylation status of MGMT, p16, and DAP-K genes was evaluated by methylation-specific PCR in 20 primary HNSCC tumors. Histopathologically negative surgical margins of hypermethylated tumors were collected, and their methylation status compared with the primary tumor status. RESULTS: Promoter hypermethylation in at least one of the three tested genes was detected in 65% (13 of 20) of tumors. MGMT was hypermethylated in 50% (10 of 20), DAP-K in 45% (9 of 20), and p16 in 20% (4 of 20) of tumors. Methylation status was analyzed in 35 margins from 11 of 13 patients showing promoter hypermethylation in the tumor tissue. Identical methylation events were seen for at least one gene in primary tumor and surgical margins in 9 of 11 cases (82%). Association was found for gene-specific hypermethylation status in tumors and paired surgical margins, and gene-specific concordance was 63% for MGMT (kappa = 0.24), 90% for DAP-K (kappa = 0.74), and 90% for p16 (kappa = 0.79). CONCLUSIONS: Our results support the hypothesis that detection of gene promoter hypermethylation in HNSCC tumor cells-free surgical margins may be a helpful biomarker to identify molecularly altered fields in areas adjacent to the tumor.

Prognostic relevance of CD105+ microvessel density in HNSCC patient outcome.

Angiogenesis is essential for the development and progression of malignant tumours, and there is increasing evidence that microvessel density (MVD) can be considered an indirect marker of neo-angiogenesis. However, there is still disagreement concerning the clinical relevance and prognostic significance of MVD in head and neck squamous cell carcinomas (HNSCCs). MVD was evaluated in 127 HNSCC patients by means of immunohistochemistry using monoclonal antibodies (mAbs) against CD34 and CD105 (endoglin), which has recently been described as a potent marker of neo-vascularisation in various malignancies. MVD was expressed as the mean number of vessels/mm2. The mean CD34+ and CD105+ MVD values were significantly higher in T3-T4 tumours and those in an advanced clinical stage; furthermore, CD105+ MVD was significantly higher in N+ tumours. The patients with a high CD105+ MVD had a significantly shorter disease-free and overall survival; CD34+ MVD was not associated with survival. Similarly, in the subset of lymph-node negative patients, higher CD105+ MVD values were significantly associated with either OS and DFS. Multivariate analysis showed that a high CD105+ MVD was the only independent marker of tumour recurrence or death. Our data suggest that CD105+ MVD may represent an additional prognostic factor in HNSCC patients providing more accurate data for the determination of prognosis and management in the subset of lymph node negative patients.

13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group.

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

beta-carotene supplementation in patients radically treated for stage I-II head and neck cancer: results of a randomized trial.

This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients.

Gemcitabine and vinorelbine in recurrent head and neck cancer: pharmacokinetic and clinical results.

OBJECTIVES: To evaluate the pharmacokinetic parameters, efficacy and toxicity of a combination of gemcitabine (GEM) and vinorelbine (VNB) in recurrent heavily pre-treated squamous cell head and neck carcinoma. MATERIALS AND METHODS: Twenty-four patients previously treated with concomitant chemo-radiotherapy (n = 13), surgery plus radiotherapy (n = 10) and surgery + concomitant chemo-radiotherapy (n = 1) were enrolled; 7 patients had received one or more courses of palliative chemotherapy. Twenty patients had a local-regional recurrence and 4 patients had metastases. The doses were 1200 mg/m2 for GEM and 30 mg/m2 for VNB on days 1 and 8 every 21 days; a maximum of 6 cycles was allowed. Pharmacokinetic investigations were performed on 9 patients receiving GEM and VNB. As a PK control, a second group of 5 patients was given GEM as single agent, at the same doses and with the same i.v. infusion length. RESULTS: Twenty-four patients received a total of 135 cycles (median per patient, 5). Neutropenia was the most frequent side-effect (92% of patients; grade 3-4 in 50%). The overall response rate was 25% which included 1 of 24 complete responses (4%) and 4 of 24 partial responses (21%). Responses were observed only in patients with good prognostic characteristics. The median response duration was 5.5 months (2-16 months) and the overall median survival was 9 months (range, 2-25+). Vinorelbine serum levels showed no evidence of any pharmacokinetic interaction with GEM; most of all, no rebound in VNB disposition can be produced by GEM pre-administration. CONCLUSION: The GEM-VNB combination has a palliative role in patients with favourable characteristics; the results seem no better than those observed with VNB alone. Moreover, this drug association does not alter the pharmacokinetic profile of both drugs, also compared to GEM monotherapy.

Postoperative adjuvant chemoradiotherapy in older patients with head and neck cancer.

BACKGROUND: In head and neck cancer, the locoregional failure of patients with positive margins, vascular or perineural invasion, and extracapsular spread is high and results in poor survival. OBJECTIVE: To assess the effect of adjuvant chemoradiotherapy in improving treatment outcomes among older patients with head and neck cancer. METHODS: Forty patients undergoing radical surgery (median age, 73.5 years [range, 70-78 years]) were enrolled (35 men and 5 women; Eastern Cooperative Oncology Group performance status, grade 0-2). Disease sites included the oral cavity (10 patients), oropharynx (12 patients), hypopharynx (8 patients), and larynx (10 patients); pathological TNM classifications included T1 N2 (8 patients), T2 N1-2 (12 patients), T3 N0-2 (8 patients), and T4 N0-2 (12 patients), with the following poor prognostic factors: positive margins (6 patients), vascular invasion (14 patients), neural invasion (16 patients), and extracapsular spread (26 patients). All patients were treated with carboplatin (30 mg/m2 on days 1-5 of weeks 1, 3, and 5) concomitant with radiotherapy (54.0 Gy to all risk volumes plus 10.0 Gy to high-risk volumes; 5 daily fractions of 1.8 Gy each per week). RESULTS: No grade 4 toxicity was observed. Grade 3 toxicity included mucositis (10 patients), neutropenia (6 patients), dermatitis (2 patients), and thrombocytopenia (1 patient). The radiotherapy dose administered was 52.0 Gy to all risk volumes plus 10.0 Gy to high-risk volumes. Thirty-two patients (80%) received 3 cycles, 6 (15%) received 2 cycles, and 2 (5%) received 1 cycle. Three-year survival was as follows: disease-free survival, 58%; overall survival, 64%; and local control, 79%. CONCLUSIONS: Adjuvant chemoradiotherapy may be successful in fit older patients. The results of adjuvant chemoradiotherapy were better than those observed in a comparable group treated with radiotherapy alone and were similar to those observed in a younger group with the same poor prognostic factors treated with adjuvant carboplatin plus radiotherapy.

Docetaxel and vinorelbine: an effective regimen in recurrent squamous cell esophageal carcinoma.

Vinorelbine and docetaxel are two effective drugs in esophageal cancer; our purpose was to evaluate efficacy and toxicity of a combination of these drugs in recurrent squamous cell esophageal cancer. Twenty patients previously treated with concomitant chemoradiotherapy (n = 14), surgery alone (n = 2), surgery plus radiotherapy (n = 2), or concomitant chemoradiotherapy + surgey (n = 2) were enrolled. Thirteen patients had a local-regional recurrence, two patients had metastases, and five patients had both. The doses were 80 mg/m(2) for docetaxel and 20 mg/m(2) for vinorelbine on d 1 every 21 d for a maximum of six cycles. Twenty patients received a total of 106 cycles (median per patient, 5). Neutropenia was the most frequent and severe side effect (grade 4 in 80%; grade 3 in 20%). The overall response rate was 60%, which included 3 of 20 complete responses (15%) and 9 of 20 partial responses (45%). Median response duration was 7 mo (2-50+). Overall median survival was 10.5 mo (range, 2-55+). A dysphagia improvement was observed in 81% of patients. In conclusion, the data from this phase II study indicate that this combination is effective in recurrent heavily pretreated patients with a short-lasting manageable toxicity.

Playing a brass instrument after total laryngectomy: a case report.

BACKGROUND: A brass instrument is a musical instrument in which the tone is produced by vibration of the lips as the player blows into a tubular resonator. The case of a professional brass player who continued his activity after total laryngectomy, with insertion of a voice prosthesis in a tracheoesophageal shunt, is reported. METHODS: A videoendoscopic and videofluoroscopic study of the patient during brass playing was conducted. RESULTS: A nonvibrating, open neoglottis during brass playing was found on videoendoscopy. Videofluorography revealed an enlarged hypopharynx, a thick neoglottis while playing at lower tone; at higher pitch the tongue base was retracted, the neoglottis was thin and stretched, and the subneoglottic area was extremely enlarged. CONCLUSION: The case reported shows that the insertion of a voice prosthesis in a tracheoesophageal shunt seems to create a regulating airflow system sufficiently advanced to play a brass instrument, further reducing the disability of laryngeal speakers.

Prognostic impact of HER-2/neu expression on squamous head and neck carcinomas.

BACKGROUND: HER-2/neu gene amplification and protein overexpression have been identified in various solid tumors, but its prognostic relevance in head and neck squamous cell carcinoma (HNSCC) is still controversial. METHODS: The study investigated the expression of HER-2/neu oncoprotein in HNSCC and sought possible correlations to various clinicopathologic parameters. Expression of HER-2/neu oncoprotein was assessed in archival tumor tissues from 87 untreated HNSCC patients by immunohistochemical technique. Data were correlated with both the clinicopathologic parameters and patient survival. RESULTS: A high membranous HER-2/neu protein expression level was found in 39% of patients. Multivariate analysis indicated that HER-2/neu protein expression and pN lymph-node status were independent prognostic factors for disease-free survival. CONCLUSIONS: HER2/neu overexpression and its relationship with survival suggest that new therapeutic approaches targeting epidermal growth factor receptor (EGFR) family receptors could provide a new way of treating HNSCC patients with HER2/neu-positive neoplastic lesions.

Constitutive expression of interleukin-18 in head and neck squamous carcinoma cells.

BACKGROUND: Interleukin (IL)-18 is a potent immunomodulatory cytokine promoting TH-1 and cytotoxic immune responses through interferon (IFN)-gamma induction. The aim of this study was to investigate the production of IL-18 by squamous cell carcinoma of the head and neck (HNSCC). METHODS: The expression of IL-18 was analyzed by reverse transcriptase-polymerase chain reaction, Western blot, and ELISA in untreated and 5-fluorouracil (5-FU)-treated HNSCC cell lines. Immunohistochemical analysis was performed on tumor specimens from 16 patients with primary invasive HNSCC. RESULTS: We have demonstrated that HNSCC cell lines express IL-18 at the mRNA, as well as the protein, level. However, the IL-18 protein was expressed intracellularly and predominantly released as an unprocessed inactive 24-kDa form. After exposure to 5-FU, the processed form of IL-18 was detected in the supernatants of both HNSCC cell lines. CONCLUSIONS: These results indicate that HNSCC cells are a potential source of IL-18 cytokine. The finding that the exposure to 5-FU can elicit its processing suggests a novel target for immunomodulatory intervention in patients with HNSCC.

Overexpression of p27BBP in head and neck carcinomas and their lymph node metastases.

BACKGROUND: p27(BBP) is a regulator of ribosome assembly and an essential nuclear and cytoplasmic component of eukaryotes. METHODS: We investigated the immunochemical distribution of p27(BBP) in head and neck carcinomas, in the associated normal mucosa, and in regional lymph nodes. RESULTS: p27(BBP) is detectable in mucosal cells but is overexpressed in carcinomas, highly concentrated in large polymorphous nucleoli, and even larger and more evident in lymph node metastatic foci. Western blotting confirms increased p27(BBP) in carcinomas versus normal mucosa and also in metastatic versus normal lymph nodes. The overexpression of p27(BBP) corresponds to mRNA upregulation in carcinomas. Unexpectedly, a 52-kDa band specifically reacting with antibodies to p27(BBP) was observed in several carcinomas. CONCLUSIONS: p27(BBP) alterations are common events in the transition to malignancy and are probably involved in squamous carcinoma progression. Immune reagents raised to p27(BBP) may provide additional diagnostic tools for surgical pathology of tumor boundaries and lymph nodes. The 52-kDa band may represent an abnormal form of p27(BBP) expressed by transformed airway epithelia.

Improved survival with perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral cavity and oropharynx.

BACKGROUND: The current randomized, multicenter, Phase III trial was conducted to determine whether the disease free interval and overall survival of patients with T2-T4,N0-N3,M0 squamous cell carcinoma (SCC) of the oral cavity or oropharynx could be extended through the combination of surgery (and radiotherapy, if required) with perilymphatic recombinant IL-2 (rIL-2). METHODS: Patients with a resectable T2-T4,N0-N3,M0 SCC of the oral cavity and oropharynx were assigned randomly to receive surgery and radiotherapy or to receive IL-2, surgery, and radiotherapy. Five thousand units of rIL-2 were injected around the ipsilateral cervical lymph node chain daily for 10 days before surgery. After surgery, contralateral 5-day rIL-2 courses were administered monthly for 1 year. The differences in disease free and overall survival between the two groups of patients were evaluated statistically. RESULTS: Two hundred two patients finished the study. No significant complications related to rIL-2 were encountered, and surgery and radiotherapy were not hampered by its prior administration. Multivariate analysis conducted to determine the extent to which survival was influenced by rIL-2 and the other variables showed that rIL-2 significantly lengthened disease free survival (P < 0.01) and that this resulted in longer overall survival (P < 0.03). CONCLUSIONS: The data emerging from this trial indicate that perilymphatic administration of low, nontoxic doses of rIL-2 is a simple and manageable way to delay recurrences of SCC.

Docetaxel, carboplatin and concomitant radiotherapy for unresectable squamous cell carcinoma of the head and neck: pharmacokinetic and clinical data of a phase I-II study.

Concomitant chemoradiotherapy is the most effective treatment of unresectable head and neck cancer. Docetaxel and carboplatin are two active drugs that potentiate radiotherapy. Thirty patients (median age = 56 years; median Eastern Cooperative Oncology Group performance status = 1) received radiotherapy (70 Gy, 2 Gy/d, 5 d/wk) concurrent with carboplatin AUC 0.3 to 0.5 on day 1-5, weeks 1, 3, 5, 7, and docetaxel 15 to 25 mg/m2 on day 4 of weeks 2, 4, and 6. Site of unresectable squamous cell carcinoma was as follows: oropharynx, 41%; hypopharynx, 27%; oral cavity, 16%; and larynx, 16%. Stage was III in 13% and IV in 87%. In 11 patients, pharmacokinetic parameters were evaluated. Acute G4 toxicity was as follows: neutropenia, 20%; mucositis, 33%. We had the following acute G3 toxicities: mucositis, 40%; neutropenia, 37%; dermatitis, 23%; and anemia, 13%. The maximum tolerated dosage was area under the curve 0.5 for carboplatin and 20 mg/m2 for docetaxel. Median radiotherapy dose was 69 Gy, and 175 out of 210 courses (83%) were administered. At the end of the treatment, we had 20 complete responses (CR) (67%), 9 partial responses (30%), and 1 no change (3%). After radial neck dissection, 2 patients achieved a CR (overall CR = 73%). After a median follow-up of 2.5 years, we had a 3-year local progression-free survival of 85%, failure-free survival of 69%, and overall survival of 60%. A significant increase of Cmax of carboplatin concentration was noted at the beginning of weeks 3, 5, and 7. Total plasma platinum raises during each course of 5 days of carboplatin without reaching a steady state. Carboplatin, docetaxel, and concomitant conventional radiotherapy is a feasible and effective treatment of unresectable head and neck cancer. The concurrent administration of two drugs does not alter pharmacokinetic drug behavior compared with single-agent data.