Karsten Jørgensen

A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85

PURPOSE A multicenter randomized and balanced double-blind trial with the objective of assessing the efficacy and tolerance of nimorazole given as a hypoxic radiosensitizer in conjunction with primary radiotherapy of invasive carcinoma of the supraglottic larynx and pharynx. PATIENTS AND TREATMENT Between January 1986 and September 1990, 422 patients (414 eligible) with pharynx and supraglottic larynx carcinoma were double-blind randomized to receive the hypoxic cell radiosensitizer nimorazole, or placebo, in association with conventional primary radiotherapy (62-68 Gy, 2 Gy per fraction, five fractions per week). The median observation time was 112 months. RESULTS Univariate analysis showed that the outcome (5-year actuarial loco-regional tumor control) was significantly related to T-classification (T1-T2 48% versus T3-T4 36%, P = 0.0008), neck-nodes (N- 53% versus N+ 33%), pre-irradiation hemoglobin (Hb) concentration (high 46% versus low 37%, P = 0.02) and sex (females 51% versus males 38%, P = 0.03). Overall the nimorazole group showed a significantly better loco-regional control rate than the placebo group (49 versus 33%, P = 0.002). A similar significant benefit of nimorazole was observed for the end-points of final loco-regional control (including surgical salvage) and cancer-related deaths (52 versus 41%, P = 0.002). This trend was also found in the overall survival but to a lesser, non-significant extent (26 versus 16%, 10-year actuarial values, P = 0.32). Cox multivariate regression analysis showed the most important prognostic parameters for loco-regional control to be positive neck nodes (relative risk 1.84 (1.38-2.45)), T3-T4 tumor (relative risk 1.65 (1.25-2.17)) and nimorazole (relative risk 0.69 (0.52-0.90)). The same parameters were also significantly related to the probability of dying from cancer. The compliance to radiotherapy was good and 98% of the patients received the planned dose. Late radiation-related morbidity was observed in 10% of the patients, irrespective of nimorazole treatment. Drug-related side-effects were minor and tolerable with transient nausea and vomiting being the most frequent complications. CONCLUSION Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects.

Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: Report from the DAHANCA 2 study

Between October 1979 and May 1985, 626 patients with pharynx and larynx carcinoma were randomized to two different split-course radiation regimens and given either misonidazole (MISO; 11 g/m2) or placebo during the initial 4 weeks of treatment. Patients in the different treatment groups were evenly distributed among stages. The small number of females (136) gave an uneven distribution, thus making analysis difficult. The results show that females had a statistically better loco-regional control (45 vs. 33%; 5-year actuarial value). Overall, the MISO treated group did not have a significantly better control rate than the placebo groups (37 vs. 34%). However, a difference was found in patients with pharynx carcinomas (38 vs. 27%; p less than 0.05). The pre-irradiation hemoglobin (Hb) concentration was found to be a prognostic parameter. In females, loco-regional control for IIb values below or above 8 mmol/l were 37 and 47%, respectively. In males, the same values were below or above 9 mmol/l 26 and 38%. Hb influence on local control was only seen in supraglottic and pharynx tumors. This effect was independent of tumor size, which also was of prognostic value. In addition Hb concentration and MISO had an apparent additive effect. Thus in the male pharynx group, placebo patients with low Hb had a 14% disease rate compared to 40% in MISO treated patients with Hb above 9 mmol/l. MISO induced significant peripheral neuropathy in 26% of the treated patients, whereas other drug related side effects were minimal and tolerable.

Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation

PURPOSE Accelerated repopulation of tumor cells during radiotherapy has been suggested as an important cause of treatment failure in squamous cell carcinoma of the head and neck. Due to tumor heterogeneity, not all tumors may benefit from accelerated radiotherapy at the expense of a lower total dose. This analysis evaluates the impact of histological differentiation on loco-regional control in relation to treatment duration. PATIENTS AND METHODS A total of 501 patients with advanced supraglottic and pharyngeal squamous cell carcinoma with known histopathological grading were treated with planned split-course (191 patients) or continuous radiotherapy (310 patients) in two consecutive randomized controlled trials. Irradiation was given 2 Gy per fraction, 5 fractions per week to a dose of 66-68 Gy in 9.5 or 6.5 weeks, respectively. RESULTS Overall, split-course and continuous treatment resulted in a 5-year loco-regional control of 30% and 41% (P = 0.007), respectively. However, the detrimental effects of split-course were only found in moderately and well-differentiated tumors, where the 5-year tumor controls were 38% and 21% after continuous and split-course treatment, respectively (P = 0.001). In contrast, in poorly differentiated tumors loco-regional control was obtained in 44% of the cases for continuous and 40% for split-course treatment (P = 0.63). CONCLUSIONS It is suggested that the ability to accelerate repopulation may be lost by dedifferentiation, and that prolongation of the overall treatment time only lead to reduced loco-regional control in well to moderately differentiated tumors.

Influence of Late Side-Effects Upon Daily Life After Radiotherapy for Laryngeal and Pharyngeal Cancer

The influence on daily life from long-term side-effects was studied in patients treated more than 5 years ago with radiotherapy for laryngeal and pharyngeal cancer. Forty-six patients were asked to participate in telephone interviews and 44 participated. Only a minority (10%) stated serious problems related to the treatment. Problems related to the voice and severe xerostomia were especially mentioned. Half of the patients treated for pharyngeal cancer, complained of xerostomia and had occasionally a feeling of being handicapped. Social relations were impaired in 10% of the patients and 10% had retired due to their cancer or therapy related side-effects. It is concluded that radiotherapy seems to be a well tolerated treatment with relatively little impairment of the daily life in patients with laryngeal cancer. In patients with pharyngeal cancer, xerostomia is a major problem, which often persists more than 5 years after treatment.

Epidermoid carcinoma of the larynx. VI. Histologic grading in the clinical evaluation.

A multifactorial microscopic grading of malignancy was performed on a clinically well examined series of 129 patients with laryngeal carcinoma. The microscopic score was statistically significantly correlated to the frequency or regional lymph-node metastases and to the death rate. It afforded important supplementary information for the T-classification and for the prognosis. Microscopic grading is an essential supplement to the clinical evaluation of risk groups.

Nimorazole as a hypoxic radiosensitizer in the treatment of supraglottic larynx and pharynx carcinoma. First report from the Danish Head and Neck Cancer Study (DAHANCA) protocol 5-85

Between January 1986 and September 1990, 442 patients with pharynx and supraglottic larynx carcinoma were randomized to receive the hypoxic cell radiosensitizer nimorazole (NIM) or placebo in association with a course of conventional primary radiotherapy. A preliminary analysis including the first 288 patients showed that the stratification parameters were significant (3-year actuarial local-regional tumor control, p less than 0.05) for sex (females 52% vs males 34%), tumor size (T1-T2 47% vs T3-T4 32%) and pre-irradiation hemoglobin (Hb) concentration (high 41% vs low 34%). Overall, the NIM group showed a significantly better local-regional control rate than the placebo group (46% vs 32%). There was an apparent additive effect of Hb concentration and NIM. Thus, in the male group, placebo patients with low Hb had a 23% control rate compared to 46% in NIM treated patients with Hb above 9 mmol/l (p less than 0.05). The similar effect in females could not be evaluated due to the small number of women with this disease. NIM was well tolerated and drug-related side effects were minor and tolerable, with transient nausea and vomiting as the most frequent complication. A final conclusion of the study must await an evaluation including all patients and a longer observation time.

Cancer of the Larynx: Treatment Results after Primary Radiotherapy with Salvage Surgery in a Series of 1005 Patients

The aim of this study is to present and discuss the results of initial radiotherapy with salvage surgery and to compare them with those from centres where primary surgery is the prevailing principle. The series comprised 1005 consecutive patients treated during the period 1965-1998. Salvage surgery was performed if patients had residual tumour or developed recurrence. Disease-specific survival (DSS) and crude survival (CS) after 5 years, among 643 patients with glottic carcinomas treated with curative radiotherapy was 88.6% (SE =1.3) and 65.3% (SE =2.0), respectively. Among T1 glottic carcinomas the locoregional control was 88%, i.e. 88% of patients were cured after radiotherapy alone, and the DSS was 99%, both evaluated after 5 years, i.e. the salvage surgery added approximately 11% to the survival of T1 glottic patients. Only 4% (12/312) of T1 glottic patients had laryngectomies. Locoregional control among T2 glottic cases was 67% and the DSS 88%, but, 18% (41/233) of patients lost their larynx. The corresponding results among T3 glottic cases were 30% and 59%, i.e. the organ preservation was close to 50%. Among patients with supraglottic carcinomas, the two estimates were 44% and 63%, respectively. Compared with our results, recent results published in the literature after initial laser surgery of T1 glottic carcinomas indicate that there are only minor differences in DSS and organ preservation, but it is generally agreed, but not proven, that voice quality after radiotherapy is better. T2 glottic carcinomas treated by initial supracricoid partial laryngectomy in a selected series have yielded very high DSS rates with better organ preservation than was observed in the present series. As to T3 glottic carcinomas, initial surgery does not produce better survival rates than those produced in the present series but our organ preservation is higher. The treatment of patients with supraglottic carcinoma has benefited from optimization of radiotherapy during recent decades. The role of initial laser surgery is as yet undecided.

Hypopharyngeal cancer: Results of treatment based on radiation therapy and salvage surgery

Objectives The purpose of this study is to present the treatment results and to identify possible prognostic indicators in patients with hypopharyngeal squamous cell carcinoma (HPC).

Lymph node metastases from laryngeal and pharyngeal carcinomas--calculation of burden of metastasis and its impact on prognosis.

A total of 1069 patients, 739 with newly diagnosed laryngeal and 330 with pharyngeal cancer, were seen at the Centre for Head and Neck Cancer, Odense University Hospital during the period 1965-1992. Of those with laryngeal carcinoma, 1% (5/499) of the glottic and 29% (68/232) of the supraglottic cases had primary lymph node metastases. The frequency of metastases in patients with primary endolaryngeal tumours was highest at the inlet of the larynx--38%--decreasing gradually distally to 1% at the level of the vocal cords. Metastases occurred among patients with pharyngeal carcinoma in 66% (218/330). All patients received primary radiotherapy, except for the 10 who were subjected to surgery. The calculation of the burden of lymph node metastases was based on the volume formula of an ellipse, and could be carried out on 280 of the 291 patients with metastases. The calculated volumes ranged from 1-1413 cm3. These were divided into 3 groups according to size. A Cox multivariate regression analysis, using crude and disease specific survival as endpoints, revealed the burden of metastasis to be an independent, prognostic factor.

Prognostic factors in papillary and follicular thyroid carcinomas : p53 expression is a significant indicator of prognosis

To identify clinical and histologic prognostic factors and to investigate whether immunohistochemical detection of p53 expression might contain prognostic information, a retrospective study of patient and tumor characteristics was performed in 225 cases of papillary and follicular thyroid carcinomas. The analyses were based on cause‐specific and crude survival. In univariate analysis, age at diagnosis, tumor size, presence of distant metastases, histology (papillary contra follicular type), extrathyroidal invasion, necrosis in primary tumor, and p53 expression were significant prognostic indicators. For 211 patients (96%) all information was available and Coxs proportional hazard model was applied. The authors found that age, distant metastases, necrosis in primary tumor, extrathyroidal invasion, and p53 expression were significant prognostic factors. Analyses of cause‐specific and crude survival gave similar results. The authors conclude that age at diagnosis, presence of distant metastases, necrosis in primary tumor, and extrathyroidal invasion are important prognostic factors, and that immunohistochemical detection of p53 protein in the primary tumor is a significant and independent prognostic indicator, which might be of value in the treatment planning in patients with papillary or follicular thyroid carcinomas.