A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time.

BACKGROUND AND PURPOSE: To compare in a phase III study the loco-regional control, disease-free survival and overall survival induced by an accelerated regimen (AF) as compared with conventional regimen (CF) and to analyze the early and late post-radiation morbidity in both arms. MATERIALS AND METHODS: Patients with age < or = 75, WHO 0-1, suitable for a radical course of radiotherapy T1-T3, N0, M0, stage of glottic and supraglottic laryngeal cancer were randomized to either CF: 66Gy given in 33 fractions over 45 days or AF: 66Gy given in 33 fractions over 38 days (2 fractions every Thursday). A total of 395 patients were included from 05.1995 to 12.1998. RESULTS: Early toxicity: At the end of radiotherapy patients treated with AF complained for more severe reactions than patients treated with CF. In 8 weeks after treatment completion patients treated with AF complained only for more severe pain on swallowing (P=0.027). In 4 months after treatment completion all types of toxicity except for skin teleangiectasia (P=0.001) were similar in the two groups. Loco-regional control: comparison between CF and AF showed no difference in terms of loco-regional control (P=0.37). CONCLUSIONS: The improvement in AF in terms of loco-regional control is estimated to be 3-5% in comparison with conventional regimen and is not significant. The intensity of reactions after 4 months was similar in both arms, what suggests the possibility of further shortening of the overall time by few days or enhancing the total dose within the limits of acceptable morbidity.

Normobaric oxygen as a sensitizer in radiotherapy for advanced head and neck cancer.

The aim of this study was to evaluate radiosensitizing effect of normobaric oxygen breathing in radiotherapy for advanced head and neck cancers. Forty seven patients with advanced squamous cell carcinomas of the head and neck (7% in Stage III and 93% in Stage IV) were entered in the study. Breathing the pure, normobaric oxygen was given for 15-20 min in the treatment room. Irradiation started immediately after oxygen breathing. Conventional, megavoltage radiotherapy to the total doses in the range of 46-67.5 Gy was used. The control group was 46 patients with the same diagnosis and stage treated by radiotherapy alone. Locoregional tumor control was 36% in the study group compared to 15% in the control (p < 0.05). Mean survival time was 15.8 and 11.8 months, and 3-year survival was 19% and 2%, respectively (p < 0.05). Survival depended on total tumor dose and total nodal dose. No significant influence of the tumor location on local control and importance of the size of dose per fraction and overall treatment time were found. The most common failure in both groups was persistent tumor. Mean recurrence time was 5 months in the study group and 8 months in the control. Present results suggest that the use of normobaric oxygen breathing prior to irradiation could increase effectiveness of conventional radiotherapy for advanced squamous cell carcinomas of head and neck.

A feasibility study of concomitant boost radiotherapy for patients with cancer of the supraglottic larynx.

Between February 1988 and December 1989, 65 patients with supraglottic cancer completed a course of concomitant boost radiotherapy. Cases with N3 disease, a Karnovsky performance score less than 70, age above 70 years, or a second primary cancer were not eligible for the study. Distribution of the patients was: Stage T1-T2 30%, T3-T4 70%, N0 68%, N+ 32%. The total dose ranged from 60 Gy to 76 Gy (median 66 Gy); overall treatment time ranged from 36 to 56 days with a median of 42 days. The daily dose during the first 4 weeks was 1.8 Gy, and during the last 2 weeks it was 1.6 Gy b.i.d. with a 4- or (after September 1988) 6-h interval. The clinical impression was that the early mucosal reactions were acceptable but more severe than after conventional treatment, with confluent membranous mucosal reaction being observed in 54% of the patients. Also, this reaction was significantly more frequent in patients treated with a 4-h interval (68%) than with a 6-h interval (41%) between the daily fractions. To relieve severe dysphagia, narcotics were required in 22% of the patients. The follow-up time ranged from 22 to 50 months, median 34 months. Treatment-requiring late complications were observed in 8 patients, and the 3-year actuarial risk was 17% with 95% confidence limits (6%, 27%). Two of these patients had severe complications: one of them required a temporary tracheostomy due to arytenoid edema and the other developed a laryngo-cutaneous fistula which healed after pharmacological treatment. Actuarial 3-year local-regional control was 59% (46%, 71%) and 3-year actuarial crude survival 55% (42%, 67%). There was no significant difference in the incidence of late complications or tumor control between the two groups of patients treated with a 4- or 6-h interval between the daily fractions. This study shows that the concomitant boost regimen tried here is feasible, but also stresses that the interval between dose fractions should be 6 h or more.

Concomitant boost radiotherapy of supraglottic cancer--preliminary results, morbidity.

Forty-two patients with supraglottic squamous cell carcinoma were irradiated with Co60 using concomitant boost technique, a variant of accelerated fractionation. This technique is characterized by administering the boost as a second daily fraction during the basic wide-field irradiations. Daily dose in the first 4 weeks was 1.8 Gy and during the last 2 weeks it was 1.6 Gy twice daily with 4-6 hours separation. Total dose ranged from 60 to 76 Gy, median 66 Gy. The treatment time ranged from 36 to 56, median 42 days. Acute mucosal reactions were more severe than those of conventional irradiation but acceptable. The follow-up time ranged from 9 to 31 months, median 16 months. The actuarial 18 months survival for all patients was 75%. The actuarial 18 months control for primary site and lymph node was 75% for T1-2 stage, and 47% for T3-4 stage. Severe late complications were not observed so far.

[Results of 3-stage treatment: (I) corticotherapy, (II) linear acceleration and (III) orbital decompression in 206 patients with malignant Graves ophthalmopathy]. / Wyniki 3-etapowego leczenia: (I) kortykoterapia, (II) akcelerator liniowy i (III) dekompresja oczodlów, 206 chorych z wytrezeszczem zlosliwym w chorobie Graves-Basedowa.

There is no, so far, a rational method of therapy based upon the etiology of autoimmune Graves' ophthalmopathy. As a malignant Graves' ophthalmopathy we defined the most severe eye changes leading to the sight loss or permanent disability of vision which are classified as exceeded class 3c according to the eye changes classification of the American Thyroid Association [27]. The aim of the study was to develop the most efficacious method of therapy for malignant Graves' ophthalmopathy. The material consisted of 206 patients treated according to the 3-stage method: 1-st--corticotherapy, 2-nd--radiotherapy, including linear accelerator, 3-rd--orbital decompression. Moreover, in four patients plasmapheresis was applied and in additional five cyclosporine was administered. In all 206 patients the estimation of the results of the treatment was based on the Donaldson ophthalmopathy index [4]. It has been proved that corticotherapy combined with linear accelerator radiotherapy has been the most efficacious method of treatment. It has also the least number of side effects. Orbital decompression as the 3-rd stage of treatment was employed in those cases in which the previous two stages of medical therapy were unsuccessful.

[Early results of combined treatment (induction chemotherapy and radiotherapy) of patients with squamous cell carcinoma of the oropharynx]. / Wczesne wyniki leczenia skojarzonego (chemioterapia indukcyjna i napromienianie) chorych na raka plaskonablonkowego gardla srodkowego.

The results of combined treatment (induction chemotherapy followed by irradiation) in 23 patients with locally advanced squamous cell carcinoma of the oropharynx were presented. Chemotherapy program included Cisplatin 100 mg/m2 i.v. in day 1 and 5-fluorouracil 750 mg/m2 i.v. on day 1-5. The chemotherapy was administered every 3 weeks for maximum 3 cycles. Complete response in 15 patients (65%), stabilization in 4 patients (17%) and progressive disease was found in 3 patients (14%). 20 patients were irradiated with radical intention. Complete response was found in 9 patients (45%) after radiotherapy. Treatment was relatively well-tolerated. Out of 17 patients with at least 6 months' follow-up (range 6-24) 6 patients are alive with no evidence of disease. We estimate the postirradiation reaction as slightly more severe than after radiotherapy alone. The reaction did not influence the prescribed way of fractionation.

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses: acute and late effects.

The early responses of normal tissues of the oral cavity and oropharynx in 498 patients, and the slowly-developing responses in 268 patients who survived a minimum of 18 months after radiotherapy for squamous cell carcinoma were analyzed. The severity of acute responses correlated with dose intensity. The incidence of severe late responses increased with increase in dose per fraction and was characterized by a low alpha/beta ratio. Severe late responses were significantly associated with severe acute responses independently of dose per fraction and total dose, and were also ameliorated slightly by protraction of treatment time suggesting that some late effects were, at least partly, a consequence of acute injury. Probability of local tumor control correlated with severity of acute response, suggesting that excessive protraction of overall treatment time to minimize acute toxicity may compromise local control of the tumor. There was no demonstrable correlation between the volume of tissue irradiated and the severity of acute or late response.

[Comparison of the effectiveness of different methods of irradiation using metronidazole as a radiation-sensitizing agent in patients with laryngeal cancer. Controlled clinical studies]. / Porównanie skutecznosci róznych metod napromieniania z uzyciem metronidazolu jako radiouczulacza u chorych na raka krtani. Kontrolowane doswiadczenie kliniczne.

Randomized controlled clinical trial has been carried out in the Oncology Center in Warsaw and Medical Academy in Lódz to assess the effectiveness of application of Metronidazole as radiosensitizer of hypoxic cells in patients with squamous cell laryngeal cancer treated by Cobalt60 irradiation in the years 1982-1986. Clinical estimation has been obtained by comparison of the effectiveness of four selected methods of dose fractionation (conventional, dynamic, dynamic with Metronidazole, irradiation twice a day) in which NSD and TDF have been comparable (1950, 116). Metronidazole has been applied intraorally six times for a total treatment with 6 g doses. The tolerance of the drug has not been very good: 72% of patients has nausea and/or vomiting. No other side effects have been observed. Major mucosal reactions appeared in patients in which the dose have been fractionated by non conventional method (large fractions, twice daily irradiation). No statistically significant differences in the immediate effect of the radiotherapy and 3 year survival among the groups of patients treated by investigated methods have been found.

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: tumor dose-response and repopulation.

In a retrospective study, local control of the primary tumor in 498 squamous cell carcinomas of the oral cavity and oropharynx was analyzed with respect to initial tumor volume, total dose after normalization for variations in fraction size, and to overall treatment time. Primary tumors were grouped into 4 sites, tongue (175), oral cavity including floor of mouth, faucial pillar, soft and hard palate and gingiva (210), tonsil (72) and buccal mucosa (41). Total doses of 60Co irradiation ranged from 30 Gy to 72 Gy, overall treatment times from 15 to 80 days and dose per fraction from 1.8 to 6 Gy. The large number of patients and diversity of dose fractionation patterns permitted assessment of the independent contributions to treatment outcome of stage, fraction size and overall treatment duration. The following conclusions were drawn: (1) Overall treatment time influenced strongly the probability of local tumor control. Over the interval of about 30-55 days used in treating most of this series of patients, an increase of 60 cGy per day, on average, was required for a constant control rate. (2) The increase in dose was attributed to accelerated tumor clonogen growth rate. Such accelerated growth could be a major determinant of failure in protracted regimens. (3) The accelerated rate of regrowth was similar for all tumor sites and stages. (4) The dose for tumor control was relatively independent of variations in fraction size within a range of about 1.6 Gy to 3 Gy: the alpha/beta value in the linear quadratic isoeffect equation was at least 15 Gy. (5) Local control at the primary site required an average of about 3 Gy more for each increase in T stage. This increase most likely reflected an increased number of tumor clonogens, not a decreased tumor cell radiosensitivity. (6) The probability of control at the primary site was less likely if lymph nodes were positive, but this association was only shown to be statistically significant for primaries classified here as oral cavity and oropharynx, not tonsil, tongue or buccal mucosa. (7) After allowing for differences in treatment parameters, especially for heterogeneity in overall treatment times, tumor control probability increased steeply with increase in total dose. (8) A general principle of radiotherapy, at least for squamous carcinomas of head and neck, should be to deliver the desired fractionated dose regimen without unnecessary interruptions and in the shortest time compatible with no reduction in dose below that tolerated by the late-responding normal tissues.