Induction chemotherapy followed by concurrent chemoradiotherapy in advanced head and neck squamous cell carcinoma.

BACKGROUND: A phase II study was carried out to investigate an induction regimen with cisplatin, paclitaxel followed by radiotherapy concurrent with weekly cisplatin for locally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Stage III-IV disease patients were eligible. Two cisplatin (100 mg/m2) and paclitaxel (175 mg/m2) courses were administered every 21 days followed by standard fractionated external beam radiotherapy (approximately 70 Gy), concomitant to weekly cisplatin (30 mg/m2). RESULTS: Thirty-five patients were enrolled: over 70% had unresectable disease with bulky lesions. Grade 3-4 neutropenia developed in 14% and G3 mucositis in 23%. Locoregional control was achieved in 51%. Median time to progression and overall survival were 10,7 and 17 months respectively; 2- and 3-year survival rates were 30% and 25% respectively. CONCLUSION: Our induction two-drug regimen followed by chemoradiotherapy with concurrent weekly cisplatin was well tolerated with low acute toxicity and good locoregional control and survival rate.

Molecular metastases markers in head and neck squamous cell carcinoma: review of the literature.

It is now widely accepted that the presence of lymph node metastases is a negative prognostic factor in head and neck squamous cell carcinoma. It follows that the ability to determine the presence of micro-metastases or the metastatic potential of a tumour at an early stage would condition the therapeutic strategy and evolution of this type of tumour. Prediction of the metastatic potential of head and neck squamous cell carcinoma is still, today, entrusted to clinical and histological evaluation of the tumour. However, the high percentage of relapse in this tumour shows the inadequacy of these parameters in predicting metastatic potential. Furthermore, progress made over the last ten years in understanding the molecular mechanisms involved in the process of neoplastic tumour progression has led to the identification of molecules that can be used as potential prognostic markers of head and neck squamous cell carcinoma. There are many molecules involved in the process of forming metastases. This process represents the final stage of a multistep model, in which alterations occur to genes that are important for growth, proliferation and migration, to which are added variations in the expression of molecules involved in the process of homeostasis of the extra-cellular matrix, of angiogenesis and lymphangiogenesis, favouring tumour invasion and the formation of metastases. This review of the literature shows that the tumour invasion process is associated with numerous molecular alterations that might be used as potential prognostic molecular markers. However, none of these alterations is univocally associated with the metastasization used in clinical practice. Further studies on larger series and on a larger scale, such as genome studies, and preclinical studies on markers used as targets in specific therapies, will provide a valuable contribution to their use in clinical practice in the short term.

Current role of chemotherapy in exclusive and integrated treatment of malignant tumours of salivary glands.

In the management of salivary glands carcinomas, surgery is the treatment of choice. Post-operative radiotherapy is indicated in cases with high risk of loco-regional relapse. Radiotherapy is also standard treatment in cases that are inoperable at onset. Chemotherapy plays a palliative role. Today, the integration between radiotherapy and chemotherapy, which provides increased local control, represents a significant step forward. This integration is important since 5-year survival in tumours with high grade histology is approximately 50%. Overall incidence of metastases is approximately 25%. Primary locations of metastases are lungs, liver, bone, central nervous system and other organs. In cases of metastatic disease, chemotherapy plays only a palliative role.

Ifosfamide in the treatment of head and neck cancer.

Ifosfamide (IFO) has demonstrated activity in recurrent/metastatic squamous cell head and neck carcinoma with an overall response rate of 24-26%. Better results are reported for chemotherapy-naive patients; in heavily pretreated cases results are poor and toxicity unacceptable. Cisplatin-IFO combination in stage III-IV is probably more active than IFO alone (ORR = 60-72 vs. 50%) but is indicated in patients who desire aggressive treatment and are physically able to tolerate the drugs. The carboplatin-IFO scheme is better tolerated than the cisplatin-IFO regimen with superimposable clinical results (ORR = 69%; CR = 15%). Carboplatin-taxol-IFO is one of the most active regimens in recurrent (ORR = 59%; CR = 17%) and in locally advanced (ORR = 81%; CR = 31%) head and neck cancer. Its role in the multidisciplinary treatment of advanced head and neck cancer is under investigation. In recurrent/metastatic undifferentiated nasopharygeal carcinoma, IFO combinations have proven to be effective as first- and second-line treatment.

Update and perspectives on non-surgical treatment of salivary gland malignancies.

Surgery is the treatment of choice for major and minor salivary gland malignancies. Herein, the role of radiation and medical treatment in the multidisciplinary management of salivary gland tumours is discussed. Neutron irradiation and hyperfractionated external beam mega voltage irradiation improve local control. Combination of three dimensional conformal radiotherapy and intensive-modulated radiation therapy provide better local tumour delineation, better field design to encompass the tumour allowing dose escalation to target while sparing the surrounding normal tissue. Cisplatin-based chemotherapy provides a response rate > or = 45%, in a palliative setting. Concomitant chemo-radiotherapy could improve local control. Recent studies evaluated the expression of molecular targets in salivary gland carcinomas (c-kit = 53-90%, EGFR = 25-85%, c-erb-B2 = 11-58%, p53 = 11-67%, H ras = 18%); these targets are very important since new targeted drugs are now available. Anti-androgen therapy might have a role in the management of patients with ductal carcinoma. These new targeted drugs could be integrated with chemotherapy and radiotherapy in the treatment of locally advanced/metastatic salivary gland malignancies.

Study of ethmoidal mucosa in a population at occupational high risk of sinonasal adenocarcinoma.

The occurrence of nasal adenocarcinomas was first described in 1965. Since 1988 these tumors have been accepted as an occupational disease for woodworkers in Italy. There are several underlying reasons why there is interest in studying the ways in which sinonasal adenocarcinomas occur. Often diagnosed at advanced stages of development because their symptoms are non-specific, these tumors are associated with a high mortality rate. A multidisciplinary study protocol was developed in this investigation. The aim was to identify the factors and conditions that promote sinonasal tumor growth in a population at risk due to occupational exposure to wood dust. Sixty-eight carpenters with a minimum of 10 years exposure to wood dust were studied. The control group comprised 81 volunteers. The patients underwent the following protocol: completion of a case report form, physical examination, evaluation of nasal cavity patency, clinical laboratory tests and histological study of the nasal mucosa. Our study provides significant evidence of the elevated incidence of pavimentous metaplasia in workers occupationally exposed to wood dust. In addition, it underscores a significant deficit of immunoglobulin A in such workers compared to the controls. However, we did not find, as reported elsewhere in the literature, a statistically significant difference between cases and controls as regards nasal symptoms and hyperemia of the nasal mucosa. Our study showed that, even in the absence of evident sinonasal lesions, it is still possible to determine an increased incidence of morphofunctional changes in subjects occupationally exposed to wood dust. Our findings may lead to the identification of occupational groups prone to elevated risk of the disease.

Differential expression and topography of adhesion molecules in laryngeal and oropharyngeal carcinomas.

This work describes the different patterns of expression of integrins and extracellular matrix proteins in normal and transformed mucosa in laryngeal and oropharyngeal carcinomas. Samples from each tumor group were sectioned and examined by immunohistochemistry using monoclonal antibodies raised against integrin chains (alpha2, alpha3, alpha6, beta1 and beta4) and their ligands (laminins 1 and 5, collagen type IV and two fibronectin isoforms: ED-A and ED-B). Controls were provided by samples of tumor-free laryngeal and oropharyngeal mucosa that had been removed during the surgical procedure. We found that the known distinct topographical pattern of integrins and the continuity of basement membrane components was altered in both groups but that the extent of changes was significantly more marked in oropharyngeal tumors, which are known to be more infiltrating and diffusive and to have a bad prognosis. These molecular patterns of expression can be used as an additional prognostic factor as they suggest a greater biological tumor aggressiveness of oropharyngeal tumors. We suggest that performing immunohistochemical analysis on biopsy samples may help in selecting the correct therapeutic strategy for these tumors and enable more accurate follow-up. The above-mentioned molecules may become part of the diagnostic toolbox of head and neck surgical pathologists.

Role of nasal valve in the surgically corrected nasal respiratory obstruction: evaluation through rhinomanometry.

The aim of this study was to evaluate the improvement of nasal flow and the fall of nasal resistance in 50 patients that underwent rhinoseptoplasty in our department and discuss the relative importance of valvular and septal deformities in nasal airway obstruction. Fifty consecutive patients underwent rhinoseptoplasty to improve nasal obstruction caused by severe septal deviation, external or internal valvular incompetence, or any combination of the three. We excluded patients with minor septal curvatures, septal perforations, or turbinate hypertrophy. Preoperative and postoperative rhinomanometry was performed on all 50 patients. In all 50 patients, septal and/or valvular surgery lowered nasal resistance in 90% of cases. Septoplasty alone with medial and basal osteotomies did not improve nasal flow (p < 0.4), whereas the correction of valvular obstruction alone increased nasal airflow in a statistically significant way (p < 0.0001). Moreover, patients with both valvular incompetence and septal deviation represented the group in which the greatest preoperative obstruction and the greatest postoperative improvement occurred. Nasal valvular function should be assessed with rhinomanometry in all preoperative rhinoplasty patients with airway obstruction. In many cases, valvular effects may surpass septal deviation as the primary cause of nasal airflow obstruction.

Survival in patients with recurrent squamous cell head and neck carcinoma treated with bio-chemotherapy.

BACKGROUND: We have shown that rIL-2 administration in recurrent head and neck cancers induces a tumor-specific T-lymphocyte reactivity and tumor regression; in a pilot study we have shown a safe and effective administration of rIL2 after cisplatin + 5-fluorouracil. Long-term results are not known. METHODS: Thirty patients with recurrent-persistent head and neck cancer were treated with cisplatin (100 mg-m(2)) d.1,5-fluorouracil (1 gr-m(2)-d c.i. 96 h), and SQ rIL-2 (4.5 M IU day 8 to 12 and 15 to 19) every 3 weeks. RESULTS: The overall response rate was 53.3% (95% CI; 34.4-72.3%): 26.6% complete response (CR) (8 patients) and 26.6% partial response (PR) (8 patients); 6 patients had SD (20%), 8 had PD (26.6%). The median follow-up was 36 months (range, 28-44). The median CR duration is 16.2 months (8.5-39+); the median survival duration of this group has not been reached. The median PR duration was 7.2 months (3-10); the median survival was 13.3 months (10-26). The median overall survival was 14 months. CONCLUSIONS: The most impressive finding is the very long survival of CRs patients. This outcome has been reported in other cancer patients with a CR after IL-2 therapy.

Qualitative and quantitative evaluation of some vocal function parameters following fitting of a prosthesis.

The insertion of a prosthesis and restoration with pectoralis major myocutaneous flaps for patients subjected to total pharyngolaryngectomy is a technique now universally accepted; however the literature on the subject is lacking. Our study considers 10 patients subjected to total pharyngolaryngectomy and restoration with pectoralis major myocutaneous flaps who were fitted with vocal function prostheses and a control group of 50 subjects treated with a total laryngectomy without pectoralis major myocutaneous flaps and who were fitted with vocal function prostheses. Specific qualitative and quantitative parameters were compared. The quantitative measurement of the levels of voice intensity and the evaluation of the harmonics-to-noise ratio were not statistically significant (p > 0.05) between the two study groups at either high- or low-volume speech. On the contrary, statistically significant differences were found (p < 0.05) for the basic frequency of both the low and the high volume voice. For the qualitative analysis seven parameters were established for evaluation by trained and untrained listeners: on the basis of these parameters the control group had statistically better voices.

Pharyngocutaneous fistula as a complication of total laryngectomy: review of the literature and analysis of case records.

Pharyngocutaneous fistula is the most common complication of total laryngectomy. The management of this problem increases hospitalization time and delays initiation of postoperative radiotherapy, where indicated. To identify factors predisposing to the development of pharyngocutaneous fistula, we reviewed the postoperative courses of 293 patients who underwent total laryngectomy at our clinic. General factors taken into account were concurrent diseases such as diabetes, liver diseases, or chronic anemia; local factors included radiotherapy before and after surgery, preoperative tracheostomy, type of cervical lymph node removal, and method of pharyngeal closure. We then compared our data with those reported in the literature by other authors. Last, we applied the Fisher exact test to a correlation we found between the higher incidence of fistula in patients with diabetes, liver diseases, or anemia. The local factor that turned out to be statistically most significant for the development of fistula was preoperative radiotherapy.

Adjuvant radiotherapy influences the survival of patients with squamous carcinoma of the head and neck who have poor prognoses.

The treatment of carcinoma of the head and neck in recent years has improved significantly, chiefly thanks to progress in surgery and radiotherapy. Despite these advances, the survival statistics reported in the literature show no appreciable evidence of radical improvement. The aims of this study were to evaluate the impact on survival achieved with the combination of surgical and postoperative radiotherapy in patients with advanced head and neck carcinomas and to identify the prognostic value of several host- and tumor-related factors that can influence the results of combined treatment. We retrospectively reviewed the medical records of 394 patients with stage III and IV carcinoma of the head and neck, of whom 170 (43%) underwent surgery alone and 224 (57%) received combined surgery and postoperative radiotherapy. The 394 patients were stratified for a set of variables including the patient's condition, the characteristics of the tumor, and the modality of treatment. Univariate analysis revealed that coexistent medical diseases, the size and site of the primary lesion, the stage of the tumor, and certain pathologic features had a negative impact on survival. Multivariate analysis showed that the removal of lymph nodes and postoperative radiotherapy can have a positive influence and can improve the prognosis. We compared the survival rates of the patients treated with surgery alone with those of the patients who underwent combined treatment, and we observed that the two survival curves were comparable, even if there was a bias because the combined treatment group consisted of patients with negative prognostic factors. The meaning of these results, compared with data from the literature, has been discussed.

Problems in reconstructive surgery in the treatment of carcinoma of the hypopharyngoesophageal junction.

BACKGROUND AND OBJECTIVES: Thirty percent of carcinomas of the pyriform sinus manifest generally with infiltrations in the cervical esophagus. In recent years, progress in reconstructive surgery has broadened surgical indications to include tumors previously managed with palliative measures alone. In some cases, radical surgery has been extended to creating safer resection margins, with more and more indications for circular pharyngectomy. Lesions involving the hypopharyngoesophageal junction pose particular problems; furthermore, the high rate of synchronous or metachronous tumors warrants the indication for total esophagectomy, which requires complex reconstructive techniques. METHODS: We report on a series of 21 patients who underwent pharyngocoloplasties after receiving total pharyngolaryngoesophagectomy. RESULTS: With regard to the oncologic results, after a follow-up of 2-60 months, 9 patients had no evidence of disease, 5 patients died during the postoperative course, 2 patients survived with disease, 4 died with disease, 1 died from metachronous breast carcinoma, and 7 underwent reintervention. CONCLUSIONS: In cases in which reconstruction by gastric pull-up is considered risky, if not contraindicated, pharyngocoloplasty represents a particularly reliable treatment option. The limits and advantages of the technique are discussed. The procedure permitted us to reconstruct the digestive tract, without encountering problems any more serious than those a normal gastric pull-up procedure would pose.

Staging of head and neck squamous cell carcinoma using the MET oncogene product as marker of tumor cells in lymph node metastases.

In head and neck squamous cell carcinomas (HNSCC), metastasis to cervical lymph nodes is a major determinant of patient outcome. To detect metastases, we used the MET oncogene as marker, which encodes the receptor for hepatocyte growth factor/scatter factor, mediating epithelial cell motility and invasiveness. The MET gene is expressed in epithelia and over-expressed in carcinomas of specific histotypes, but not in lymphatic tissue. A total of 151 lymph nodes from 20 squamous cell carcinomas were studied with both in-depth histology and end-point and real-time quantitative RT-PCR. MET-encoded sequences were found in 61 of 151 nodes (40%), of which 24 (16%) were found metastatic by in-depth histopathology. Parallel routine histopathologic analysis of 654 lymph nodes from the same cases identified 36 metastases (5%). Real-time quantitative RT-PCR was used to measure MET gene-specific mRNA in normal tissues, primary tumors and lymphatic metastases and showed a 2-8-fold increased expression in tumor cells which metastasize. RT-PCR for 3 cytokeratins expressed in HNSCC (K4, K10 and K13) proved to be less sensitive in detecting occult lymphatic metastases. Western blot analysis demonstrated the presence of the full-size MET receptor in primary tumors and lymph node metastases; immunohistochemistry showed receptor localization in tumor cells. Altogether, these data demonstrate that the MET gene product is a valuable marker with which to detect occult tumor cells in lymph nodes, thanks to its high expression in metastatic cells. After RT-PCR analysis we were able to attribute a more advanced stage to 10 out of 20 HNSCC cases, including 5 cases classified as tumor-free after routine histopathology.

Current role of radiotherapy in the treatment of locally advanced laryngeal carcinomas.

BACKGROUND AND OBJECTIVES: During the past few years, radiotherapy (RT) has been increasingly used in combination with surgery in the treatment of locally advanced laryngeal carcinomas to improve survival rates in patients with more extensive tumors. METHODS: This is a retrospective study of a large series of stage III and IV laryngeal carcinomas, and postoperative RT was indicated for some of these cases. We retrospectively reviewed the medical records of 380 patients with stage III and IV tumors, of which 163 (43%) underwent surgery only and 217 (57%) received surgery and postoperative RT. RESULTS: The survival rates of patients who underwent surgery and RT were comparable to those of patients who underwent surgery only, but the former group was composed of subjects suffering from negative prognostic factors. CONCLUSIONS: The indications for combined treatment should be correlated with the prognostic factors to increase the survival rate of patients with stage III and IV laryngeal carcinoma.

Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas.

A metastatic cancer develops by accumulation of mutations in genes that control growth, survival and spreading. The latter genes have not yet been identified. In lymph node metastases of head and neck squamous cell carcinomas (HNSCC), we found mutations in the MET oncogene, which encodes the tyrosine kinase receptor for Scatter Factor, a cytokine that stimulates epithelial cell motility and invasiveness during embryogenesis and tissue remodeling. We identified two somatic mutations: the Y1230C, known as a MET germline mutation which predisposes to hereditary renal cell carcinoma, and the Y1235D that is novel and changes a critical tyrosine, known to regulate MET kinase activity. The mutated MET receptors are constitutively active and confer an invasive phenotype to transfected cells. Interestingly, cells carrying the MET mutations are selected during metastatic spread: transcripts of the mutant alleles are highly represented in metastases, but barely detectable in primary tumors. These data indicate that cells expressing mutant MET undergo clonal expansion during HNSCC progression and suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis.

[Post-parotidectomy Frey's syndrome. Treatment with botulinum toxin type A]. / Sindrome di Frey post parotidectomia. Trattamento con tossina botulinica di tipo A.

The Frey's syndrome, manifest after parotid trauma, is characterized by head and neck hyperemia and abundant sweating of the hyperemic skin in response to gustatory stimuli. The use of the botulin toxin to treat the symptoms in patients with Frey's syndrome has been described in numerous studies. For some time up until now our Center has achieved excellent results using the group A botulin toxin to overcome the hypertonus of the cricopharyngeal muscle in patients who had undergone laryngectomy and were rehabilitated with voice button. We have sought to extend the use of this toxin to Frey's syndrome, a relatively frequent complication of parotidectomy. A total of 86 patients participated in the study: 41 males (47.6%) and 45 females (52.4%) ranging in age from 25 to 77 years (average age 51 years). Of these patients 7 (8.1%) had undergone post-operative radiotherapy. Of the 86 patients studied, 18 referred significant symptoms in terms of abundance and frequency. The syndrome was considered severe if the symptoms were present at each meal and if the patient indicated a significant worsening of his quality of life. Intermittent episodes were indicated by 22 patients. The remaining 46 (43.5%) did not complain of any symptoms. The exact extension of the cervicofacial gustatory sweating was evaluated using the Minor test and the involved region was divided into 1 square centimeters sections. The amount of skin surface involved ranged from 10 to 80 square centimeters. The type A neurotoxin was frozen and was reconstituted with a sterile saline solution at a final concentration of 2.5 UI/0.1 ml. The intracutaneous infiltration was performed without anesthesia, infiltrating 0.1 ml of solution, containing 2.5 UI of toxin into the center of each 1 square centimeters section. Statistical analysis was performed to evaluate the potential relationship between how long the treatment was effective, incidence of recurrence, seriousness of the crises and the following variables: age, sex, histology, cutaneous surface involved, injected dose of botulin toxin and post-operative radiotherapy. In the group of 18 patients with severe symptoms (20.9%) the benefit was immediate in all cases although the recurrence rate was 50%. The Frey's syndrome symptoms disappeared within 7 days of infiltration. In the group of 22 patients with less severe involvement (25.5%), the treatment gave positive, definitive results in 16 patients (72.7%). Those patients whose symptoms persisted were treated a second time with an infiltration of 2.5 UI per square centimeters. We feel that the use of the type A botulin toxin is the most appropriate treatment for the Frey's syndrome. In fact, such treatment offers the following advantages: it is effective within 7 days, has limited side effects, can be applied on an outpatient basis, is inexpensive and is positively considered by the patients.