Prognostic significance of cell kinetics in laryngeal squamous cell carcinoma: clinicopathological associations.

A consecutive series of 99 untreated patients undergoing radical surgical resection for stage I-IV laryngeal carcinomas has been studied prospectively. Our purpose was to analyze the predictive relevance of proliferative variables studied [proliferating cell nuclear antigen (PCNA) expression, volume-corrected mitotic (M/V) index, and S-phase fraction (SPF)] on clinical outcome in relation to DNA ploidy and clinicopathological features. All of the patients were followed up for a median of 32 months (range, 5-58 months). A weak, but significant, positive correlation was found between M/V and PCNA indices (except the PCNA weighted mean index:labeling index ratio) or these indices and SPF. At univariate analysis, node positivity (P < 0.05), poor histological grade (P < 0.01), DNA aneuploidy (P < 0.01), a high SPF (P < 0.01), and a high M/V index (P < 0.05) proved to be related significantly to quicker relapse, whereas T4 (P < 0.05), subglottic site (P < 0.05), DNA aneuploidy (P < 0.01) and a high SPF (P < 0.01) were related significantly to shorter overall survival. With multivariate analysis, a high SPF (> 12.1%) and histological grade (G3) were related to the risk of relapse (relative risk, 8.65 and 5.45, respectively), whereas only a high SPF was related independently to the risk of death (relative risk, 7.30). Our study has identified SPF, in addition to histological grade, as an important biological indicator in laryngeal carcinomas.

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. METHODS: Flow cytometric DNA ploidy and S-phase fraction (SPF) measurements were performed on frozen tumor tissues from a consecutive series of 71 patients with Stage III and IV LSCC: Lysosomal cathepsin B and L activity levels were determined biochemically in matched paired sets of tumor tissue and normal mucosa samples. RESULTS: By univariate analysis, lymph node positivity, poor histologic differentiation, DNA aneuploidy, high SPF, and high tumor/mucosa ratio of cathepsin B activity were significantly related to risk of relapse, whereas only DNA aneuploidy and high SPF proved to be significantly related to risk of death. Multivariate analysis showed that high histologic grade and high SPF values (> 15.1%) were independent prognostic factors related to risk of relapse (relative risk [RR] = 3.54; 95% confidence limits [CL] = 1.05-12.0; and RR = 4.22; CL = 1.54-11.6, respectively), whereas only high SPF was related to risk of death (RR = 3.63; CL = 1.17-11.3). CONCLUSIONS: S-phase fraction is an independent predictor of relapse free and overall survival in patients with locally advanced LSCC. On the basis of these findings, SPF should be used in addition to other established prognostic factors to refine the prognostic assessment of these patients further. More studies are needed for a better evaluation of the prognostic significance of DNA ploidy and that of lysosomal cysteine proteinases in these tumors.

Vinorelbine plus cisplatin in recurrent or previously untreated unresectable squamous cell carcinoma of the head and neck.

Despite considerable progress achieved in the management of head and neck carcinomas (HNC) in the last decade, the prognosis of patients with advanced squamous cell HNC is still dismal. On the basis of the reported good activity of a new vinca alkaloid derivative, i.e., vinorelbine (VNR), we tested the combination of cisplatin and VNR in a series of patients with recurrent or previously untreated unresectable squamous cell HNC. Thirty-five patients with recurrent or previously untreated unresectable squamous cell HNC were treated with a combination of cisplatin 80 mg/m2 on day 1, plus vinorelbine 25 mg/m2 i.v. push on days 1 and 8. This cycle was repeated every 3 weeks. Analysis of response rates was carried out separately for previously untreated patients, and those with recurrent disease after surgery and/or radiotherapy. In the group of 20 patients with recurrent disease the overall response rate was 55% (95% CL 44-66%), with 3 patients (15%) showing a complete response with a mean duration of 6.2+ months and 8 patients showing a partial response with a mean duration of 8.6+ months. In the group of patients with previously untreated unresectable disease, 13 patients (87%, 95% CL 78-96%) had a major objective response with a complete response rate of 27%. This regimen was quite well tolerated, with meyelosuppression and vomiting being the most frequent toxicities. The occurrence of an acute pain syndrome following vinorelbine administration in 4 patients is noteworthy. In conclusion, this combination is active in advanced squamous cell head and neck carcinoma. However, although it may be recommended in recurrent carcinoma, the complete response rate achieved in previously untreated patients is lower than that reported with other more intensive regimens.

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.

P53 expression in stage iii-iv squamous-cell carcinoma of the larynx - an immunohistochemical study related to clinicopathological, flow-cytometric DNA analysis and prognosis.

A series of 71 patients undergoing radical surgical resection for stage III and IV laryngeal carcinoma (LC) consecutively diagnosed was prospectively studied in order to evaluate the relative weight of p53 expression in predicting clinical outcome, All the patients taking part in this study were followed up for a median of 18 months (range: 6-41 months). Positive staining for p53 protein was detected in 44 of 71 (62%) of these tumors on paraffin-embedded tissue, even in dysplastic areas. Among the clinico-pathological and biological parameters analyzed, only flow-cytometric S-phase (FCM-S) Values of turners showed a significant relationship to p53 immunostaining (p=0.01). With Kaplan-Meier estimation, in multivariate analysis only high FCM-S (>15.1) was independently related to risk of relapse (RR=5.82), while both FCM-S and site (subglottis) were related to risk of death (RR=6.83 and RR=14.3, respectively). These findings indicate that p53 immunoreactivity, though of no utility as a prognostic indicator, probably plays a role in the early stages of LC tumorigenesis.

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.

Chemotherapeutic treatment of recurrent and/or metastatic nasopharyngeal carcinoma: a retrospective analysis of 40 cases.

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

Head and neck carcinoma with distant metastases: a retrospective analysis of 44 cases treated with cisplatin-based chemotherapeutic regimens.

The rarity of medical reports on the chemotherapeutic management of head and neck cancer metastatic to distant organs prompted us to review the effect of cisplatin-based regimens in this clinical setting. Out of 44 eligible patients, 10 patients (23%) achieved a CR, 16 patients (36%) has a PR, 7 (16%) no change, and 11 (25%) progressed. Patients with rhinopharyngeal carcinoma showed a 69% overall response rate, while those with other head and neck carcinomas had a 54% overall response rate. No preferential site of response was detected. The difference in mean survival of responding patients between the rhinopharyngeal group and the non-rhinopharyngeal group was statistically significant (P < 0.05). Responding patients survived longer than non responders (P < 0.05 in both groups). Interestingly, 3 patients in the rhinopharyngeal cancer group survived more than 2 years from the start of chemotherapy for metastatic disease. These data strengthen the observation that rhinopharyngeal carcinoma, even with distant metastases, responds to chemotherapy better than other carcinomas arising in the head and neck region. Moreover, although survival is still dismal, cisplatin-based systemic chemotherapy seems an effective palliative treatment for metastatic head and neck cancer.

Hydroxyurea modulates 5-fluorouracil antineoplastic activity in advanced head and neck carcinoma pretreated with chemotherapy.

After informed consent 21 patients with advanced head and neck cancer resistant to folinic acid/5-fluorouracil (FA/5FU + cisplatin) were treated with weekly FA/5FU plus low dose hydroxyurea (HU) to evaluate if HU could further modulate 5FU antineoplastic activity. Five patients achieved a partial response (23.8%) which was short-lived (mean duration 6.5 months). Three patients (14%) had stable disease and 13 (62%) progressed. Among responders, four patients had epidermoidal carcinoma and one had clear cell carcinoma. Treatment was well tolerated and 5FU-related toxicity was not apparently worsened by the addition of HU. The most frequent toxicities were nausea/vomiting (81%), diarrhea (52%) and leukopenia (57%). Grade 3 nausea/vomiting and leukopenia were recorded in only 19 and 9% of cases, respectively. One patient had grade 1 cutaneous toxicity and a second patient showed a hand-foot syndrome. These results suggest that HU may further positively modulate 5FU antineoplastic activity.

High-dose folinic acid and 5-fluorouracil plus cisplatin on a weekly schedule in the treatment of advanced cancer of the head and neck.

A group of 60 patients with advanced head/neck cancer were treated with high-dose folinic acid (500 mg/m-2/week-1) plus 5-fluorouracil (400 mg/m-2/week-1 on day 1, and cisplatin (20 mg/m-2/week-1) 24 h after folinic acid infusion was completed. Out of 55 evaluable patients, 10 patients (18%) experienced a complete response with a mean duration of 11.4+ months, 25 patients had a partial response (45%) of 6.7+ months, 6 patients (11%) showed a stabilization of 4.8+ months, and 14 (25%) progressed. The overall response rate was 63.6% (95% confidence limits 56.5%-69.5%). Patients pretreated with radiotherapy had a 67% overall response rate, while those pretreated with chemotherapy showed a 54% overall response rate. All patients with cancer of the oropharynx had a major response, while patients with cancer of the oral cavity had the lowest response rate. The mean survival of patients who attained a complete response was 14.5+ months. Partial responders had a mean survival of 10.6+ months, while patients who progresses survived a mean of 3.6+ months. The treatment has been very well tolerated with few cases of grade 3 gastrointestinal toxicity. Grade 1-2 leukopenia was recorded in 64% of cases, grade 1-2 nausea/vomiting in 85%. In one case therapy was stopped because of persistent diarrhoea.

Weekly 5-fluorouracil and folinic acid plus escalating doses of cisplatin with glutathione 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 glutathione 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 glutathione 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 glutathione seems to be able to reduce, at least partially, CDDP-related nephrotoxicity permitting the delivery of higher CDDP doses.