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.

Inhaled nitric oxide in the evaluation of heart transplant candidates with elevated pulmonary vascular resistance.

The reversibility of elevated pulmonary vascular resistance in heart transplant candidates is currently evaluated with intravenous vasodilators. The aim of this study was to evaluate the effects of increased concentrations of inhaled nitric oxide (20, 40, and 80 ppm) on central hemodynamics and right ventricular function in heart transplant candidates with elevated pulmonary vascular resistance (> 2.5 Wood units). Comparison was made with intravenous vasodilators, sodium nitroprusside, and prostacyclin in doses that lowered the mean arterial pressure by about 15%. Inhalation of nitric oxide did not change systemic or pulmonary arterial pressure, cardiac output, right ventricular function, or systemic vascular resistance. Pulmonary capillary wedge pressure increased and transpulmonary pressure gradient and pulmonary vascular resistance decreased (-34% +/- 4% and -36% +/- 4%, respectively; p < 0.01) during 20 ppm nitric oxide, with no further effects at higher doses. Prostacyclin and sodium nitroprusside decreased pulmonary vascular resistance (-50% +/- 6% and -33% +/- 5%; p < 0.01). Prostacyclin reduced to some extent (p = 0.08) transpulmonary pressure gradient, which was not seen during sodium nitroprusside infusion. Systemic vascular resistance decreased during both sodium nitroprusside (-37% +/- 5%) and prostacyclin (-44% +/- 4%) infusion. The pulmonary vascular resistance/systemic vascular resistance ratio, used as an index of pulmonary selectivity, was decreased by nitric oxide (p < 0.01) but not by the intravenous vasodilators. Metabolic data indicate that inhaled nitric oxide is metabolized in the same way as that formed endogenously. In conclusion, inhaled nitric oxide is a selective pulmonary vasodilator that can be used safely in the hemodynamic evaluation of heart transplant candidates with elevated pulmonary vascular resistance.

Squamous cell carcinoma of the oropharynx. Results of primary radiotherapy.

During the six-year period in 1979 through 1985, 226 patients (67 females and 159 males) with squamous cell carcinoma of the oropharynx were treated at the Finsen Institute in Copenhagen. Ages ranged from 35 to 86 years with an average of 64 years for females and 61 years for males. The primary tumour was most often situated in the lateral wall (55%) and the anterior wall (25%). Thirty-nine per cent of the tumours were in stage III and 40% in stage IV. The primary treatment was radiotherapy, in this period given with three different treatment schedules, one continuous and two split-course. The 5-year crude survival rate in the total material was 36% and the corrected 5-year survival rate 45%. Females had a higher loco-regional control rate than males, but there was no significant differences between the sexes concerning survival. The tumour stage (IUCC, 1978) was an important prognostic factor for both loco-regional control and survival. No significant differences could be found between the three treatment schedules concerning loco-regional control or survival.

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.

Stage I glottic carcinoma: an analysis of tumour recurrence after primary radiotherapy.

During the period 1978-82, 145 patients with Stage I glottic carcinoma had primary radiotherapy at the Finsen Institute in Copenhagen. Of these, 35 patients developed recurrence, corresponding to a local control rate of 76%. Following salvage surgery a further 14% of the patients became free of disease for a minimum follow-up of 3 1/2 years or until death. A total local control rate of 90% was obtained. Possible prognostic factors in patients developing local recurrence following radiotherapy were assessed. No reliable predictor of treatment failure could be identified: sex, age, haemoglobin concentration, smoking and drinking habits, tumour stage, location, size and differentiation, were all found to be of no significance.

Squamous cell carcinoma of the oral cavity. An unselected material from a 5-year period.

Three hundred and four patients with squamous cell carcinomas of the oral cavity were treated at the Finsen Institute in cooperation with the ENT-surgical departments between 1978 and 1982. The primary treatment consisted of radiotherapy alone in 74%, surgery alone in 4%, and a combination of radiotherapy and surgery in 15% of the patients. Two per cent received other treatment (cryotherapy), 5% did not complete the planned radiotherapy, and 1% were not treated at all. Of 203 patients with tumour remnant or first recurrence, 45% were operated, 2% received radiotherapy, and 2% combined treatment. This treatment strategy made 38% of the patients free of disease in the follow-up period (3 1/2 to 8 years) or until the patients died from other causes. Fifty-nine per cent of the patients died from their oral carcinomas. Tumour size (T), lymph node status (N), and tumour stage were as expected important prognostic factors.

Advanced squamous cell carcinoma of the larynx.

Out of 676 patients with advanced squamous cell carcinoma of the larynx in stage III or IV, 673 patients received primary radiotherapy, either alone or in combination with surgery or chemotherapy. A significantly better survival with loco-regional control was obtained for women than for men. Also, the tumour size was of significant importance, as a better survival with loco-regional control was seen for tumours below 4 cm in largest diameter than for larger tumours. A similar advantage was seen as regards T1 and T2 tumours. There was no difference with regard to the patients' ages, tumour location, node status, or tumour stage III or IV. At 10 years, the crude survival for the total group of stage III and IV patients was 17%, corrected survival 38%.

[Early diagnosis of cancer of the oral cavity, is it a possibility?]. / Tidligere diagnostik af mundhulekraeft, er en sådan mulig?

Study of patients with oral carcinomas from the Finsen Institute in a five-year period, shows the survival to be significantly correlated to the tumour stage on referral. In order to improve the prognosis for these patients, earlier diagnosis and earlier referral for treatment to the oncological centre are necessary.

Traditional and new treatment strategies for oral squamous cell carcinomas.

308 patients with intraoral carcinomas were treated in the Finsen Institute, Copenhagen, from 1978 to 1982. As primary treatment, 73% of the patients had radiotherapy alone, 5% had operations alone, and 14% had combined treatment. After first recurrences, 45% of 204 patients were operated on. This treatment strategy kept 40% of all 308 patients free of disease for at least 3.5 years or until death. Fifty-eight percent of all 308 patients died of their oral carcinomas. The present study shows that tumor size, lymph node involvement, and total tumor stage are important prognostic factors. Old and new treatment strategies are discussed and more use of operations using modern reconstructive techniques followed by radiotherapy is recommended.

[Is earlier diagnosis of oral cancer possible?]. / Tidligere diagnostik af mundhulekraeft, er en sådan mulig?

Study of patients with oral carcinomas from the Finsen Institute in a five-year period, shows the survival to be significantly correlated to the tumour stage on referral. In order to improve the prognosis for these patients, earlier diagnosis and earlier referral for treatment to the oncological centre are necessary.

The effect of sequential methotrexate and 5-fluorouracil in patients with recurrent head and neck cancer.

Sequential methotrexate and 5-fluorouracil was given to 105 patients with recurrent head and neck cancer. All 105 patients had previously received radiotherapy in curative doses; 41 patients had also been surgically treated and 21 had received previous chemotherapy for recurrence. The treatment consisted of methotrexate 125 mg/m2, followed by 5-fluorouracil 600 mg/m2 after 1 h. Leucovorin rescue was administered after 24 h. A response was observed in 24 patients (23%), including 9 (9%) with complete response. The majority of the responders were patients with a good performance status and with primary tumour in the oropharynx. The toxicity was not negligible, as 5 patients (5%) died of treatment-related causes, mainly due to leukopenia, which was the most frequent and important complication. This sequential methotrexate/5-fluorouracil treatment-schedule cannot be recommended for recurrent head and neck cancer patients.

Tumour markers in testicular germ cell tumours. Five-year experience from the DATECA Study 1976-1980.

Since Jan. 1, 1976, nearly all new cases of testicular germ cell tumours have been included in the Danish Testicular Carcinoma Study (DATECA), and have been monitored by the tumour markers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG). During the first five years, 1058 patients participated in the investigation, but only 603 of these patients were followed by preoperative as well as postoperative marker determinations in serum. The overall prevalence of marker positivity, i.e. elevated preoperative values for AFP and/or HCG, was 8 per cent for seminoma patients and 60 per cent for non-seminoma patients. Elevated levels of serum AFP and HCG were correlated to the presence of endodermal sinus tumour and choriocarcinoma elements, respectively, in the primary tumour. The presence of increased marker concentration in serum was correlated stage (higher percentage in higher stages) and to prognosis (marker negative patients had a better prognosis than marker positive patients). Marker production by seminoma patients seems to indicate a poor prognosis, especially for HCG producing seminomas.

Biochemical markers for testicular germ-cell tumors in relation to histology and stage: some experiences from the Danish testicular cancer (DATECA) Study from 1976 through 1981.

The DATECA Project was started in January 1976 and includes all patients with testicular cancer in Denmark. During the first 6 years, 1246 patients entered the joint protocol for histology, staging, management, and clinical use of tumor markers. Only 746 DATECA patients fulfilled the claims for being ideally monitored with preoperative as well as postoperative serologic marker determinations. The overall prevalence of marker positivity, that is, elevated preoperative values of alpha-fetoprotein (AFP) and/or human chorionic gonadotrophin (HCG) was 8% for patients with seminoma and 63% for patients with nonseminomatous disease. The prevalence of increased marker concentration in serum was correlated to stage (higher prevalence in higher stages) and to prognosis (marker-negative patients had a better prognosis than did marker-positive patients). An increased concentration of AFP or HCG was correlated with the presence of a primary endodermal sinus tumor and choriocarcinoma component, respectively.