Salvatore Restivo

A pilot study of vinorelbine on a weekly schedule in recurrent and/or metastatic squamous cell carcinoma of the head and neck

Vinorelbine (VNR), 5′-nor-anhydrovinblastine, is a new semi-synthetic vinka alkaloid with selective affinity for mitotic microtubules, which has been shown to be active against several non small cell lung cancer lines in vitro [1]. VNR has been reported to yield a 34.7 % and 20 % overall response rate in patients with squamous cell lung carcinoma and bronchial adenocarcinoma respectively [2]. Moreover, VNR has been shown to be active in advanced breast carcinoma where it may induce a 30–50 % response rate depending on the extent of pretreatment [3]. We tested the activity and toxicity of single agent VNR given on a weekly schedule in a series of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCHNC).

Prognostic significance of p16INK4a alterations and 9p21 loss of heterozigosity in locally advanced laryngeal squamous cell carcinoma

The p16INK4a gene, localized within chromosome 9p21, has been identified as a cyclin‐dependent kinase inhibitor and may negatively regulate the cell cycle acting as a tumor suppressor. Genetic alterations involving the 9p21 region are common in human cancers. A consecutive series of 64 untreated patients (median of follow up 53 months) undergoing surgical resection for locally advanced laryngeal squamous‐cell carcinomas (LSCCs) has been studied prospectively. Our purpose was to investigate p16 alterations (9p21 allelic loss, hypermethylation and point mutations) and their possible association with clinico‐pathological data and flow cytometric variables (DNA‐ploidy and S‐phase fraction (SPF)), and to determine the possible prognostic role of this gene in these tumors. PCR‐based techniques were used for investigating 9p21 loss of heterozygosity (LOH) and methylation promoter status of the p16 gene. p16 mutations were detected by PCR‐SSCP (single strand conformation polymorphism) and sequencing. 9p21 LOH was detected in 16/62 (26%) informative tumors, point mutations in 5% (3/64) and hypermethylation in 9% (6/64) of the cases. p16 alterations were significantly associated with high SPF and DNA‐aneuploidy. By univariate analysis, poor histologic differentiation, stage IV, DNA‐aneuploidy and p16 point mutations proved to be significantly related to quicker relapse, whereas these same factors, and in addition high SPF, 9p21 LOH and any p16 alterations were significantly related to shorter overall survival. By Cox proportional hazards analysis only histologic grade (G3) and p16 point mutations were independently related to both disease relapse and death. Our study has identified p16 point mutations as important biomolecular indicators in LSCCs.

Flow cytometric DNA analysis and lysosomal cathepsins b and l in locally advanced laryngeal cancer. Relationship with clinicopathologic parameters and prognostic significance

Background. The traditional factors of locally advanced laryngeal squamous cell carcinoma (LSCC) have limited predictive value for the identification of high risk patients. Therefore, it is extremely important to define prognostic factors that identify the more aggressive types. Reliable and reproducible prognostic indicators are being investigated to help clinicians identify high risk groups and address more rational treatment.

TP53 Mutations and S-Phase Fraction but not DNA-Ploidy Are Independent Prognostic Indicators in Laryngeal Squamous Cell Carcinoma

To prospectively evaluate the prognostic significance of TP53, H‐, K‐, and N‐Ras mutations, DNA‐ploidy and S‐phase fraction (SPF) in patients affected by locally advanced laryngeal squamous cell carcinoma (LSCC). Eight‐one patients (median follow‐up was 71 months) who underwent resective surgery for primary operable locally advanced LSCC were analyzed. Tumor DNA was screened for mutational analysis by PCR/SSCP and sequencing. DNA‐ploidy and SPF were performed by flow cytometric analyses. Thirty‐six patients (44%) had, at least, a mutation in the TP53 gene. Of them, 22% (8/36) had double mutations and 3% (1/36) had triple mutations. In total, 46 TP53 mutations were observed. The majority (41%) of these occur in exon 5 (19/46), while the mutations in exons 6, 7, and 8 were represented in 14, 7, and 6 patients, respectively (31%, 15%, and 16%). Five LSCC patients (6%) showed a mutation in H‐Ras gene. Sixty‐three percent of the cases (51/81) were DNA aneuploidy, 14% of these (7/51) were multiclonal. Thirty‐nine patients (48%) had an high SPF value. At Univariate analysis, the DNA aneuploidy, high SPF (>15.1%), TP53 mutations and, in particular, the mutations that occur in exons 5 and 8 were significantly related to quicker disease relapse and short OS. At Multivariate analysis, the major significant predictors for both disease relapse and death were high SPF and any TP53 mutations. While histological grade G3 was an independent factor only for relapse. In conclusions, any TP53 mutations and high SPF are important biological indicators to predict the outcome of LSCC patients.

A Phase II Study of Levofolinic Acid and 5-Fluorouracil Plus Cisplatin in Patients with Advanced Head and Neck Squamous Cell Carcinoma

Forty patients with advanced squamous cell carcinoma of the head and neck (SCHNC) were treated with a combination of levofolinic acid 100 mg/m2+5-fluorouracil 375 mg/m2 in a 4-hour infusion plus cisplatin 20 mg/m2 in a 2-hour infusion for 5 consecutive days, repeated every 21-28 days. In the group of 20 previously untreated patients, a 90% overall response rate (ORR) with a 30% complete response rate (CRR) was obtained. In the group of 20 pretreated patients with recurrent and/or metastatic SCHNC, a 55% ORR with 15% CRR was achieved. This treatment was given on an outpatient basis and was generally very well tolerated with only 2 patients requiring hospitalization. Grade 1-2 gastrointestinal and hematological side effects were the most frequent toxicities. One patient had grade 4 liver toxicity, 1 had grade 4 anemia, and 1 grade 3 neurotoxicity. This treatment seems very active in both previously untreated and pretreated patients. However, in the latter group the mean duration of complete response (12.2+ months) and of partial response (7.4+ months) are, in our opinion, still unsatisfactory.

Methotrexate, Vinblastine, Epidoxorubicin, and Bleomycin as Second-Line Chemotherapy for Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck

Thirty evaluable patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck region previously treated with cisplatin-based chemotherapy were treated with a combination of methotrexate, vinblastine, epidoxorubicin, and bleomycin as second-line chemotherapy. Besides surgery and/or radiotherapy all patients had previously received chemotherapy as induction therapy or as palliation for recurrent disease. Only 20% of patients achieved a partial objective response with a mean duration of 5.6 months (range 3.2-6.2), and 30% of patients had a stabilization of disease with a mean duration of 4.2+ months (range 3.8-6.0). Patients who responded had rhinopharyngeal carcinoma, poorly differentiated histology, or they had not been previously treated with radiotherapy. All remaining patients (50%) progressed. Toxicity was significant with grade 3-4 leukopenia in 30% of cases, grade 2-3 mucositis in 40% of patients, and grade 2-3 vomiting in 43% of cases. In consideration of the dismal clinical results and of the significant toxicity recorded, we do not recommend to use this combination as second-line therapy in recurrent head and neck cancer. Further chemotherapy should be reserved to carefully selected cases with a reasonably high chance of response.

Radiosurgery in the treatment of laryngeal abductor paralysis

Abstract Abductor true vocal cord paralysis is a complex condition that requires the surgeon to perform an emergency tracheotomy to eliminate the symptom of dyspnea. Throughout the past 20 years, corrective surgery has reverted to techniques using external or endoscopic techniques. For 5 years now, we have used high frequency radiosurgery by Ellman to treat various ENT conditions in our clinic. The experience we have gained has encouraged us to use this method in endoscopic surgery as well, in the treatment of laryngeal abductor paralysis under suspension microlaryngoscopy. Twelve patients were examined between 1999 and 2002. Diagnosis was performed through flexible fiberoptic videolaryngoscopy. After describing the surgical procedure performed, we underline the advantages of radiosurgery in the treatment of abductor paralysis of the larynx.

Weekly 5-fluorouracil and folinic acid plus escalating doses of cisplatin with gluthatione protection in patients with advanced head and neck cancer

Twenty-two patients with advanced head and neck carcinoma were treated with 5FU 400 mg-2 m{-1} week and folinic acid 500 mg m-2 week-1 plus CDDP in escalating doses from 20 to 40 mg m-2 week-1 without forced diuresis. Reduced gluthatione at the dose of 1.5 g m-2 was employed to protect patients from CDDP-related nephrotoxicity. The aims of the study were: a) to evaluate the therapeutic efficacy of this schedule, and b) to evaluate reduced gluthatione as uroprotector. Out of 20 evaluable patients 14 (70 %) had a major objective response. A CR with a mean duration of 9.0+ months was achieved in 15% of the patients, a PR of 5.8+ months in 55 % of the patients, while 3 patients had stable disease and 4 progressed. It was possible to escalate CDDP up to 35 mg m-2 week{-1}, but at the dose of CDDP 40 mg m-2 week-1 the occurrence of grade 2 renal toxicity provoked a severe reduction of dose-intensity. Overall, this treatment has been very well tolerated by most patients with few cases of grade 3 gastrointestinal or hematological toxicity. In conclusion, the schedule seems effective and may be safely given to patients with advanced head and neck cancer on outpatient basis. Reduced gluthatione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.

Radiosurgery in the treatment of the glottic plane carcinoma

Abstract During the last 20 years, various conservative surgical techniques have been proposed to treat larynx cancer. On the basis of our various experiences and of the ultrastructural data on the tissues treated with radiowaves, we decided to also use radiosurgery in operations under direct microlaryngoscopy. We select 18 patients suffering from epidermoid carcinoma. These patients had been referred to our ENT clinic at the Polichnico of Palermo between 1999 and 2001. The authors describe the surgical procedures used and emphasize the advantages of radiosurgery in the treatment of larynx cancer.