Measurement of platinum in saliva of patients treated with cisplatin.

A procedure for the measurement of platinum (Pt) in the saliva of patients treated with cisplatin has been developed. The saliva is collected and solubilized in hyamine hydroxide before analysis by graphite furnace atomic absorption spectrometry using assay by standard additions. The method has an analytical detection limit of 0.025 microgram/mL and is precise, with coefficients of variation of 3-10.0% over a range of 0.05-2.0 micrograms/mL. Platinum was measured in saliva collected during an 8-h infusion of cisplatin from five patients, at the end of a 30-min infusion in nine, and 24 and 48 h later from a further 15 patients, all of whom were treated with cisplatin for squamous cell carcinoma of the neck. The platinum concentration in saliva taken at the end of a 30-min infusion was 0.27 +/- 0.23 microgram/mL (mean +/- 1 SD) but was below the detection limit of 0.025 microgram/mL at 24 and 48 h. After an 8-h infusion the salivary Pt was significantly less (0.12 +/- 0.04 microgram/mL; P < 0.05). The plasma Pt concentrations after 30-min and 8-h infusions were 2.98 +/- 1.03 and 2.54 +/- 0.59 micrograms/mL, respectively, and were not significantly different. The results indicate higher concentrations of free platinum in plasma after 30 min compared with an 8-h infusion. The monitoring of salivary concentrations of platinum may therefore provide a non-invasive way to study the unbound fraction of cisplatin in blood and facilitate optimization of cisplatin treatment.

Prospective evaluation of cell kinetics in head and neck squamous carcinoma: the relationship to tumour factors and survival.

Tumour growth rates were measured in 105 patients using in vivo incorporation of bromodeoxyuridine (BrdU) and investigated for any relationship to tumour factors or survival. The median labelling index (LI) was 8.7%, the duration of S-phase (Ts) was 14 h and the potential doubling time (Tpot) was 5.9 days. The labelling index in aneuploid tumours was significantly higher than that in diploid tumours. However the total labelling index (TLI) did not differ significantly between aneuploid and diploid tumours, and so it would seem likely that the difference in LI is due to the dilutional effect of benign tissue upon the calculation of LI in diploid tumours. The total labelling index, duration of S-phase and potential doubling time were not related to the tumour factors examined (site, T stage, N stage, stage grouping). Interim survival analysis was carried out and there was no difference in survival between those patients with high values for TLI, Ts, and Tpot and those with low values.

The treatment of primary recurrence following laryngectomy for laryngeal carcinoma.

Of the 397 patients undergoing total laryngectomy for squamous cell carcinoma by Professor P. M. Stell between 1963 and 1991, 73 are known to have suffered a local recurrence. Of these, 17 were treated by radiotherapy and/or further surgery. Secondary surgery was reserved for selected cases of peristomal and pharyngeal recurrence: of the 35 peristomal recurrences, eight were treated surgically. Previous reports of recurrence after total laryngectomy have focused on the problem of peristomal recurrence. Patients with pharyngeal recurrences can also be treated satisfactorily with microvascular surgical reconstruction techniques. Though rarely curative, secondary total pharyngectomy can be highly palliative and results in little additional morbidity.

Cisplatin-albumin complex for treatment of cancer of the head and neck.

Many patients with cancer of the head and neck are unable to receive or continue treatment with cisplatin, which is nephrotoxic, because of poor renal function. We present here, however, the case of a patient who underwent conventional cisplatin therapy but who then had to be withdrawn from treatment because of renal toxicity despite having undergone partial remission. Treatment was then changed to cisplatin in the form of a cisplatin-albumin complex which is not nephrotoxic. The patient went on to a histologically confirmed complete response and we suggest that although the cisplatin-albumin complex may not be as effective as the conventional form of the drug it offers a possible form of treatment of patients with compromised renal function who could not otherwise be treated.

Multiple cytogenetic aberrations in squamous cell carcinomas of the head and neck.

Chromosomal abnormalities in short term cultures have been investigated in 10 squamous cell carcinomas of the head and neck. Of these tumours, three demonstrated clonal chromosomal abnormalities, two showed random abnormalities and 5 patients' tumours had normal karyotypes. The 5 patients with aberrant karyotypes were all from previously treated tumours, of these, 4 patients had received radiotherapy and 1 surgery. On analysis of the three clonal tumours, two were found to be polyclonal, each with five separate clones. 116 breakpoints were demonstrated from the clonal data of these tumours, and all of the chromosomes were involved, apart from number 18. In this study we found three or more breakpoints at sites 1p36, 9q32 and 11q23. 1 of the patients investigated showed a clonal abnormality involving a breakpoint at the 11q13 site, with a further 2 patients having breakpoints at 1p22--sites previously reported to have marked clustering of cytogenetic abnormalities in oral cancer patients. Only further studies will demonstrate whether the breakpoints found are of clinical significance.

Value of grading squamous cell carcinoma of the head and neck.

We report a series of 3,294 patients with squamous cell carcinoma of the head and neck seen by one of us between 1963 and 1990. Two thousand and seven patients had a histologically proven and graded, but previously untreated, squamous cell carcinoma of the mucosal surfaces of the head and neck. These tumors had been graded previously by many different pathologists in many different hospitals, both in the United Kingdom and the United States, as well as continental Europe, over this period. Of the host factors both sex and age were associated with differentiation: 34% of patients less than age 50 had a well-differentiated tumor compared with 44% greater than age 50; 32% of women had a poorly differentiated tumor compared with 26% of men. General condition had no correlation with degree of differentiation. Site was closely associated with grading: well-differentiated tumors were more common in the mouth and larynx and poorly differentiated tumors in the pharynx. Furthermore, of poorly differentiated tumors, 19% arose from areas normally lined by keratinized squamous epithelium, 22% from a nonkeratinized area, 36% from respiratory epithelium, and 45% from areas normally covered by lymphoid epithelium. T stage had no significant correlation with differentiation. However, 46% of patients with poorly differentiated tumors had a nodal metastasis at presentation compared with only 28% of well-differentiated tumors. Distant metastases at presentation were found in 3.4% of poorly differentiated tumors compared with 1.8% of well-differentiated tumors. The survival fell significantly from 33% for well-differentiated tumors to 27% for poorly differentiated tumors. The recurrence rate at the primary site rose from 25% for well-differentiated tumors to 27% for poorly differentiated tumors, and recurrence in the lymph nodes rose from 26% to 30%. Both differences were just significant.

Tumour growth rates in squamous carcinoma of the head and neck measured by in vivo bromodeoxyuridine incorporation and flow cytometry.

The cell kinetics of 82 squamous cell carcinomas of the head and neck were studied by in vivo administration of the thymidine analogue, bromodeoxyuridine (BrdUrd). Ploidy, BrdUrd labelling index (LI), duration of S-phase (Ts), potential doubling time (Tpot) and S-phase fraction (SPF) were measured by flow cytometry on 50 microns paraffin embedded sections. The range of values obtained compared well with other in vivo cell kinetic studies of head and neck cancer. Aneuploid tumours had a significantly higher BrdUrd labelling index and SPF, and a short Tpot than diploid tumours. To validate the use of 50 microns sections for measuring cell kinetic parameters by flow cytometry a comparison of values obtained by 50 microns sections and small blocks of tissue was made. No significant difference was found between the two methods. Reproducibility of values between two consecutive thick sections was also good. We conclude that reproducible cell kinetic measurements can be made in tumour samples using 50 microns sections of BrdUrd labelled tissue.

Prognosis in mouth cancer: host factors.

A personal series of 842 patients with a tumour of the oral cavity is presented. Five hundred and twelve of these patients had a histologically proven squamous cell carcinoma, and were previously untreated. Increasing age was associated with worsening performance status. Women were older at presentation than men, and tumours of the upper part of the mouth were more common in the elderly, but there was no relation between age and histological grade or stage grouping. Sex had no correlation with performance status or histological grade. However, men were more likely to have an advanced tumour, and tumours of the floor of the mouth and alveolus were much commoner in men. There was no correlation between performance status and site or histological grade, but patients in poor general condition were more likely to have stage III-IV tumours. Multivariate analysis showed that sex had no impact whatever on survival, but survival fell with increasing age and worsening performance status. The effect of age and performance status disappeared when the survival of treated patients was adjusted for deaths due to other causes.

C-erbB-2 expression in squamous cell carcinoma of the head and neck.

Seventy-five squamous cell carcinomas of the head and neck were analysed for c-erbB-2 expression using immunohistochemical techniques with four different c-erbB-2 antibodies. No membrane staining was seen in any of the squamous cell carcinomas studied with any of the antibodies; however, c-erbB-2 cytoplasmic staining was seen in 60 per cent of the tumours. The significance of cytoplasmic staining is discussed and that it may possibly represent elevated c-erbB-2 expression in squamous cell carcinomas. C-erbB-2 cytoplasmic staining was also observed in 10 of 23 normal specimens obtained from the resection margin of the tumours. No correlations were found between positive c-erbB-2 cytoplasmic staining and any of the clinicopathological parameters or survival.

Low levels of ras p21 oncogene expression correlates with clinical outcome in head and neck squamous cell carcinoma.

We have previously demonstrated that the Ha-ras and the Ki-ras oncogenes are overexpressed in squamous cell carcinoma of the head and neck. In this study we have used the Y13-259 monoclonal antibody to p21 ras to determine if expression of the ras oncoprotein correlates with any of the clinico-pathological parameters or with survival in 69 patients with squamous cell carcinoma of the head and neck. Forty-four specimens were from patients with previously untreated tumours and 25 from patients with previously treated disease. We have found a correlation between low levels of ras expression and the disease-free survival period in patients with previously untreated tumours. Three per cent of the patients with ras negative staining were alive 60 months after diagnosis, whereas 54 per cent of the patients with positive staining were still alive after the same time period (P less than 0.05).

Squamous carcinoma of the head and neck in the young adult.

We present a series of 2305 previously untreated histologically proven squamous carcinomas of the mucosal surfaces of the upper aerodigestive tract managed by one of us in a 27-year period. 62 (2.7%) of the patients were aged 40 years or younger. The sex ratio between young and old patients was similar but, as expected, the younger patients were in better physical condition. Furthermore, 90% of young patients were treated, compared with only 78% of the older patients. Younger patients had a higher incidence of oropharyngeal tumours and lymph node metastases, but the proportion of poorly differentiated tumours, and stage T3-T4 tumours, was similar, as was the metastatic rate. The crude survival of the younger patients was 10% better than that of the older group, and adjusted (life-table) survival was 9% better, and this better survival in younger patients was significant when differing site incidence and N-stage were allowed for by multivariate analysis. The recurrence rate at the primary site was 19% in the younger patients and 15% in older patients, but this difference was not significant. The recurrence rate in cervical lymph nodes was similar in both age groups: 37% at 2 years in young patients and 38% in older patients.

Phase I trial of a cisplatin-albumin complex for the treatment of cancer of the head and neck.

1. A phase I trial of a cisplatin-albumin complex for the treatment of end-stage squamous cell carcinoma of the head and neck is reported. The complex was prepared by overnight incubation of cisplatin with human albumin at 37 degrees C. This resulted in more than 98% of the drug being bound to protein at the start of treatment. The patients were either unable to continue with or had refused conventional therapy with cisplatin. 2. The trial began at a dose of 100 mg cisplatin m-2 and was increased in 25 mg m-2 increments to 650 mg m-2. Despite the absence of the customary protective measures of pre-hydration and anti-emetic treatment no serious toxicity was encountered. 3. Unbound plasma platinum concentrations were lower than after conventional cisplatin treatment but total plasma platinum and tumour platinum concentrations were much higher. Urinary excretion of platinum was low and the incidence of nephrotoxicity was greatly diminished. Two responses were seen (one complete and one partial) in 38 patients treated and the median survival time was 109 days, compared with 151 days for patients treated conventionally with cisplatin and 56 days for untreated patients. 4. The complex is not as effective as conventional cisplatin therapy but is much less toxic, offers improved quality of life during treatment and may prove to be of benefit in patients who could not otherwise be treated.

Squamous carcinoma of the posterior pharyngeal wall.

We present 70 patients with tumours of the posterior pharyngeal wall, considering tumours of the posterior hypopharyngeal and posterior oropharyngeal wall as one unit. Almost half (45%) of the patients were in poor general condition at the time of presentation, and 60% had Stage III or IV tumours. One-third of the patients were untreated, and surgery was mainly reserved for patients with Stage I and II tumours. The larynx could be preserved in two-thirds of those undergoing surgery. The best current method of repair of the posterior pharyngeal wall after partial pharyngectomy appears to be a revascularized radial forearm flap. The median survival for patients with Stage I tumours was 236 weeks, but for patients with Stages II-IV tumours was only 33 weeks. There was no significant difference between the survival for II-IV stage groups, but there was between Group I and the rest. We identify 2 defects in the UICC classification system: lack of definition of the lateral limit of the posterior pharyngeal wall, and a gross discrepancy between size and T staging of tumours arising primarily from the posterior wall of the hypopharynx.