Thyroid carcinomas after irradiation for a first cancer during childhood.

BACKGROUND: The thyroid gland is among the most radiosensitive organs. However, little is known about the long-term risk of developing a thyroid tumor after fractionated external radiotherapy for cancer during childhood. OBJECTIVE: To study the long-term risk of developing a thyroid tumor in 4096 three-year survivors of childhood cancer treated between May 1942 and December 1985 in 8 centers in France and the United Kingdom, 2827 of whom had received external radiotherapy. METHODS: A wide range of radiation doses were given to the thyroid: 1164 children received less than 0.5 Gy and 812 received more than 5.0 Gy, the average dose being 7.0 Gy. RESULTS: After mean follow-up of 15 years (range, 3-45 years), 14 patients-all of whom had received radiotherapy-developed a clinical thyroid carcinoma. Within the cohort, the relation between radiation dose to the thyroid and risk of thyroid carcinoma and adenoma was similar to that observed in patients who received radiotherapy during childhood for other reasons, such as an excess relative risk per gray of 4 to 8, up to a few gray. In contrast, compared with thyroid cancer incidence in the general population, the standardized incidence of thyroid carcinoma was much higher than expected from the dose-response relationship estimated within the cohort and from patients who received radiotherapy during childhood for other reasons: a dose of 0.5 Gy was associated with a standardized incidence ratio of 35 (90% confidence interval, 10-87) and a dose of 3.6 Gy with a standardized incidence ratio of 73 (90% confidence interval, 28-153). We did not show a reduction in excess relative risk per gray with use of an increasing number of fractions. CONCLUSION: Although we cannot estimate the exact proportion, it is probable that some or all children who are treated for cancer are predisposed to developing a thyroid carcinoma.

Hyperfractionated radiotherapy with or without misonidazole: results of a prospective randomized study in stage III-IV squamous cell carcinoma of the head and neck.

From 1979 to 1980, 52 patients with Stage III-IV squamous cell carcinoma of the head and neck were included in a prospective randomized study on hyperfractionated radiotherapy with or without misonidazole. The radiotherapeutic schedule consisted of two weeks of treatment split by a rest-period of one month, 6 X 1.1 Gy fractions per day for 5 consecutive days (total dose: 2 X 33 Gy/30 f/5 d). Total dose of misonidazole was 12 g/m2 administered daily in 1.2 g/m2 fractions. The overall tolerance of misonidazole was good, with a neuropathy rate of 5.7%. Local control, recurrence and 3 year survival rates did not statistically differ between the two groups. The randomized trials published at the present time, including our own, suggest that misonidazole has no beneficial effect with classical, concentrated or multiple fractions per day radiotherapy.

Hyperfractionated radiotherapy in advanced squamous cell carcinoma of the head and neck.

From January, 1976 to January, 1980, 141 patients (135 males and 6 females) with Stage III and IV squamous cell carcinoma of the head and neck received a split course of hyperfractionated radiotherapy (HFR). In the first group, involving 91 patients, the therapeutic schedule was as follows: first and fourth week, 7.2 Gy per day in 8 sessions of .9 Gy from Monday to Friday, the second and third week no irradiation was given. Thus, patients were given 72 Gy total dose, fractionated into 80 sessions. Mucosal necrosis and severe hemorrhage were responsible for the death of 26 patients (28%). Therefore the therapeutic protocol was altered for the 50 patients of the second group: during the first and sixth week 6.6 Gy per day in 6 sessions of 1.1 Gy from Monday to Friday. The total dose was thus reduced to 66 Gy fractionated into 60 sessions, resulting in the decrease of toxicity. Regardless of the therapeutic protocol and site of primary, 114 patients (80%) achieved a complete remission and 8 showed a partial remission (greater than 50%), whereas no change was seen for the 19 remainders. Local recurrence appeared in 60 patients (48%). Acute mucositis and laryngeal edema regularly occurred a week after every course of HFR and were considered severe in 40 patients. In spite of toxicity, the median survival is 14 months and 22 patients are still alive in November 1981: 19 without disease, and 8 of these patients have a survival time of at least 3 years.

Relation between responses to induction chemotherapy and subsequent radiotherapy in advanced or multicentric squamous cell carcinomas of the head and neck.

Between 1984 and 1986, 85 consecutive patients with Stage III-IV or multi-centric squamous cell carcinoma of the head and neck were given three courses of chemotherapy followed by curative external radiotherapy. Induction chemotherapy consisted of either DDP (100 mg/m2, d 1) + 5 FU (1 g/m2/d, d 1-5, continuous infusion) or DDP (100 mg/m2, d4) + Etoposide (60 mg/m2/d, d 1-5, intravenously). Radiotherapy was delivered 70 Gy over 7 weeks in gross tumor and palpable nodes and 50 Gy over 5 weeks in clinically negative nodal areas. Complete response (CR) rates of both the chemotherapies were 39% for the primary and 20% for the nodes whereas partial response (PR) rates were 22% and 40%, respectively. Six months after completion of radiotherapy, 70% of the primaries and 63% of the nodes achieved complete response. The analysis of responses to chemotherapy on one hand and to subsequent radiotherapy on the other shows that the response to chemotherapy can be regarded as predictive for subsequent radiotherapy (p less than 0.001) except in T1-T2 tumors. In these early stages radiotherapy can be efficacious despite a previous failure of chemotherapy (p less than 0.01).

Analysis of late complications after rapid hyperfractionated radiotherapy in advanced head and neck cancers.

Late effects were analyzed in a series of 39 patients with a 2-year minimal follow-up who were treated by rapid hyperfractionated radiotherapy. The total dose was 66-72 Gy delivered in two series of 33-36 Gy separated by a 2-4 week rest interval. The number of daily fractions ranged from 8 to 6 and the interval between each fraction was 2 hr. Late complications consisted of cervical fibrosis, mucosal necrosis, bone necrosis, trismus, and laryngeal edema. Seventy percent of patients experienced late complications, and in 54% of cases, these reactions were considered severe, causing death in 13% of patients. No relationship was found between field sizes, dosimetric data and type and frequency of late effects. It is therefore suggested that the interval between two daily sessions in any multifractionated protocol may be of critical importance.

Localized adenocarcinoma of the lung: a retrospective study of 186 non-metastatic patients from the French Federation of Cancer Institutes--the Radiotherapy Cooperative Group.

From January 1980 to December 1984, 186 patients with non-metastatic primary adenocarcinoma of the lung were treated in 10 different French Cancer Institutes. All patients have a minimal 5-year follow-up. There were 19 Stage I, 58 Stage II, and 109 Stage III. Survival was correlated with treatment modality. Survival rates for patients treated with surgery (36 pts), surgery and radiotherapy (65 pts), or radiotherapy with or without chemotherapy (80 pts) were 44.7%, 28.5%, and 6%, respectively. In the group of patients who were operated on, local control rate was improved by adjunctive radiotherapy delivering more than 50 Gy in 5 weeks. The cumulative risk of developing distant metastasis was 37% at the end of the first year following diagnosis and 68% at 5 years. Stage of the disease, nodal involvement, and location of the primary were the main factors of prognosis.

Advanced carcinoma of the larynx: results of surgery and radiotherapy without induction chemotherapy (1980-1985): a multivariate analysis.

PURPOSE: Induction chemotherapy has been proposed in the case of advanced laryngeal cancer in order to preserve laryngeal function in those patients who are complete responders. To clarify the treatment policies, a retrospective multicentric analysis of 116 patients with advanced carcinoma of the larynx treated by radical surgery and postoperative radiotherapy was carried out in order to evaluate prognostic factors for local control and survival. METHODS AND MATERIALS: Between 1980 and 1985, 116 patients with Stage III squamous cell carcinoma of the larynx underwent radical surgery and postoperative radiotherapy with a curative intent. Treatments were very homogenous, and doses delivered were in the range of 50-65 Gy according to nodal involvement and surgical margins status. RESULTS: The local recurrence rate and the local disease-free survival rate at 5 years were 22.5% and 76.3%, respectively. Actuarial survival at 5 years was 68.3% with 44 patients still alive with no evidence of disease (NED) with more than 5 years follow-up. For both overall survival and relapse-free survival, cervical node involvement with capsular rupture was found to be the only significant adverse pronostic factor in univariate and multivariate analysis. No other parameter was predictive either for local recurrence or for survival. CONCLUSIONS: Local prognosis and survival depend largely on nodal involvement and capsular rupture while increasing doses of radiation strategy is likely to reduce the risk of local and nodal recurrence. Preservation of functional larynx is certainly an important goal to achieve when treating advanced carcinoma of the larynx, provided that local failure rate and survival be similar. In the unique randomized study previously published in the literature comparing radical surgery and postoperative radiotherapy to induction chemotherapy and radiotherapy, the local-regional failure rate was drastically increased in the chemotherapy arm. Other results from well-designed controlled studies are awaited before recommending systematic induction chemotherapy and larynx preservation in complete responders. On the other hand, testing synchronous or alternated chemotherapy vs. induction chemotherapy may address the pending questions about the optimal treatment of advanced laryngeal carcinoma.

Systematic irradiation of the vaginal vault in stage I endometrial carcinoma.

One hundred and twenty patients with clinical pathological stage I carcinoma of the endometrium were treated by total abdominal hysterectomy, bilateral salpingo-oophorectomy, and either pre- or postoperative intracavitary cesium insertion. External pelvic irradiation (45-50 Gy in 5 weeks) was given postoperatively in 36 cases, mainly for deep myometrial invasion. All the women have been followed for a minimum of 5 years. The overall 5-year survival rate is 86%. According to histological grading, the 5-year survival was 88, 83 and 57% for grades 1 (90 patients), 2 (23 patients) and 3 (7 patients) respectively. A total of 17 local and distant failures were observed: 10 patients had distant metastases, six patients had a pelvic failure and one had both. There was only one isolated vaginal recurrence. Depth of myometrial invasion was not a statistically significant indicator of outcome. Survival rates were comparable in pre- and postoperatively treated patients.

The use of a concomitant electron boost (field in the field technique) in large cervical node metastases over a shortened period.

Seven patients with large cervical node metastases were treated at the Institut Jean-Godinot using a particular scheme of accelerated irradiation. Conventional Cobalt-60 radiotherapy was prophylactically delivered to extended volumes of the neck (50 Gy in 25 fractions over 5 weeks). Within the fields of cobalt irradiation, an electron beam field was added to increase the daily dose from 2 to 3 Gy (Fletcher's field in the field technique). The increment of dose was limited to nodal area. Since no interval separated the two irradiations, involved areas were considered to receive 70 Gy in 25 fractions over 5 weeks and non-clinically involved areas to receive 50 Gy in 25 fractions over 5 weeks. In all the cases, the malignant mass diameter exceeded 5 cm. Acute tolerance was good and no major late injury was observed during the 18 months minimum follow-up period. At the end of the treatment, a complete disappearance of the tumor was observed in six out of seven cases. At the present time, four patients are still alive without evidence of disease. Slight acceleration of irradiation by the use of a concomitant electron boost is easily feasible and may provide an improvement in local control and therapeutic ratio of large cervical malignant masses in the neck.

Squamous cell carcinoma of the upper aero-digestive tract in women.

Between 1970 and 1985, 95 women presenting carcinomas of the oral cavity, pharynx or larynx, were treated at the Institut Jean-Godinot. Classification of these patients according to age shows a bimodal curve and the existence of two different populations. The main difference between groups appears to be the existence or not of tobacco intoxication. According to this criteria, the two groups of patients are statistically different in mean age (nonusers 16 years older than users, p less than 0.01) and in the site of the primary, with an excess of carcinomas of the oral cavity in the nonusers group (p less than 0.01). In contrast, no difference was found in the locoregional extension of the tumor (TNM), in the modalities and result of treatment or in the evolution and survival of patients.

Neoadjuvant chemotherapy and irradiation in multiple synchronous squamous cell carcinoma of the upper aero digestive tract.

Twenty-four patients with multiple, synchronous carcinoma of the head and neck, lung or esophagus, were treated with induction chemotherapy followed by irradiation to involved areas. Chemotherapy regimen consisted of cisplatinum either alone, or in combination with 5-FU or etoposide. Subsequently, external radiotherapy, 60-65 Gy and 70-75 Gy to the mediastinum and the head and neck areas, respectively, was carried out. Following chemotherapy, three patients (12.5%) had a complete clinical remission in both cervical and mediastinal sites. That rate was significantly increased by radiotherapy (66%). Tolerance was fair or mild even though half of the patients needed a rest break during irradiation. Follow-up ranges from 24 to 38 months. The median survival is 12 months and the actuarial survival rates are 45% and 5% at 12 and 24 months, respectively. It is suggested that induction chemotherapy will not drastically improve the overall prognosis of multiple squamous cell carcinoma of the upper aero digestive tract and that external irradiation remains a major part of treatment which should not be reduced in treated volumes, or in total dose delivered.

Results of postoperative radiation therapy in medullary carcinoma of the thyroid: a retrospective study by the French Federation of Cancer Institutes--the Radiotherapy Cooperative Group.

Between 1971 and 1989, 59 patients received external radiation therapy with a curative intent. There were 25 females and 34 males, ranging in age from 19 to 87. No patients had distant metastasis at the onset of treatment. The majority of patients had a total thyroidectomy (55/59), generally combined with neck dissection. Residual tumour was left in 11 cases, and 44 patients had positive cervical nodes. Using megavoltage radiotherapy, the whole neck and the upper mediastinum area were most often irradiated through a large anterior Y-shaped field without laryngeal shielding. The mean dose to the tumoral bed was 54 Gy. Dysphagia was observed in 32 patients (11, 17 and 5 scores were grade 1, 2 and 3, respectively). Dyspnea occurred in five cases and in two of these cases, it was considered to be severe. Local recurrences were noted in 18 (30%) patients, most of them occurring within the fields of irradiation. Parameters such as age, sex, total dose, irradiated volumes or cervical node enlargement did not modify the local control rate. The same conclusions can be drawn for distant failures. Thirty five patients are still alive and among them, 24 have no evidence of disease. The average length of survival is 70.5 months and is shortened by the occurrence of distant failures except in patients with bone metastases.

Early death during initial chemotherapy of squamous cell carcinoma of the oro- or hypopharynx.

Neoadjuvant chemotherapy produces high response rates in squamous cell carcinoma of the head and neck without increasing the survival time. Furthermore authors have observed a death rate of about 5% (up to 10%) during chemotherapy. A series of patients with an oro- or hypo-pharynx cancer, were retrospectively divided into two groups on the basis of a short (< or = 2 months) or long (> or = 2 years) survival time. Clinical, tumoral and usual biological data from either group were compared. By univariate analysis, obesity index, hemoglobin, albumin concentrations and mononuclear cell counts were lower in patients with a short survival time compared with those in the other group. On the contrary, polymorphonuclear cell and platelet counts were higher. Infection appeared to be more frequent for patients with a poor prognosis without being entirely responsible for early death. By multivariate analysis, obesity index and platelet count were both independent variables associated with prognosis. These results call for further investigation of cardiac function, inflammatory, nutritional and immunological status of patients with squamous cell carcinoma of the head and neck who were given initial chemotherapy, particularly Cisplatin and Fluorouracil.

Prognostic significance of routine clinical and laboratory data in advanced head and neck cancers.

Predictive factors for toxicity and response to chemotherapy in patients with advanced head and neck cancer are seldom reported. Therefore, from a short series of patients with a histologically proven cancer, who were treated by a neo-adjuvant protocol with cisplatin and fluorouracil, routine clinical and laboratory data were investigated. ALT (alanine aminotransferase) and Hb (hemoglobin) appeared to be predictive for efficacy. By multivariate analysis (principal component analysis), these laboratory data were involved in two independent axes: one which was considered as "inflammatory" and the other as "hepatic". Initial obesity indices were associated with the former. The predictive variables for toxicity (i.e. age, serum creatinine level, weight loss and plasma cisplatin) were probably biased in this series. Nevertheless cisplatin concentration regularly increased in each cycle. Hence it was dependent on the rank of the course. According to this preliminary study, it would be of interest to conduct future investigations on acquired protein-energy malnutrition, as well as on selected soluble mediators of cellular and humoral immune response.

Accelerated irradiation of cervical node metastases.

Accelerated irradiation combining electron beam and cobalt sources was carried out in 34 patients with large involved nodes fixed to the cervical structures (N3). Concomitant boost technique was used to reduce the overall duration of treatment from 7 to 5 weeks while maintaining the standard 70-Gy tumor dose. The first part of treatment consisted of conventional cobalt irradiation, 50 Gy delivered to the whole neck over 5 weeks. The accelerated schedule, carried out over 4 weeks, delivered an additional 1 Gy/day to the node through a circular and lateral electron beam field, for a total dose of 70 Gy to the enlarged node. In the case of an identified primary the tumor site was also boosted to the 70-Gy total dose. The rate of acute skin reactions was acceptable and there were no major mucosal complications. At the end of irradiation, 62% of patients experienced complete clinical regression; 41% subsequently had cervical recurrences. Early cervical fibrosis was limited to the over-treated area. The concomitant boost technique is a good way to accelerate irradiation without decreasing the total dose or increasing the immediate complication rate.

Iridium afterloading curietherapy in the treatment of pediatric malignancies. The Institut Gustave Roussy experience.

Between 1972 and 1980, 58 children with malignant tumors underwent iridium 192 (192Ir) curietherapy at the Institut Gustave Roussy. Data from only 45 of them were reviewed (bilateral retinoblastoma and salvage procedures were excluded). The pathologic diagnosis was rhabdomyosarcoma in 75% of cases, yolk sac tumor in 13% of cases, malignant mesenchymoma in two cases, clear cell carcinoma in two cases, and undifferentiated sarcoma in one case. The two major sites were pelvis-perineum (64.5%) and head and neck (31%). The treatment was essentially based on a combination of chemotherapy, which was adapted to the histologic type of the tumor, and curietherapy. Partial surgery was carried out in certain cases, either before chemotherapy for diagnostic purposes, or after chemotherapy to remove infiltrative residual tumor. External beam radiotherapy was used in a few cases in lymph node irradiation. The radioactive material was 192Ir, using afterloading techniques, either intracavitary or interstitially or both. The tumor dose, calculated by computerized dosimetry, was 60 to 65 Gy delivered over 5 to 7 days in the majority of cases. Two patients were lost to follow-up. Thirty-five patients (78%) are alive with no evidence of disease after a mean follow-up period of 5 years. Eight patients died, one of complications related to chemotherapy and seven of the evolution of their disease. The late-complication rate, studied in 33 patients with a minimum follow-up period of 3 years, is 18% (6/33). Curietherapy seems to be a preferable conservative treatment in children with localized and accessible malignant tumors.

Rapid hyperfractionated radiotherapy. Clinical results in 178 advanced squamous cell carcinomas of the head and neck.

The authors present a series of 178 patients with Stage III or IV squamous cell carcinoma of the head and neck treated by rapid irradiation using multiple and small fractions per day. An initial group of 91 patients (G1) received a total dose of 72 Gy in 80 sessions and 10 days, according to the following split course schedule: J1 to J5, 36 Gy in 40 sessions, eight daily fractions of .9 Gy separated by 2 hours; J6 to J20, rest period; J21 to J25, same as in J1 except that the spinal cord was shielded. This protocol was altered for the following 87 patients (G2) by lessening the total dose to 60 to 66 Gy and the number of fractions to 60. The rest period was lengthened to 4 weeks. All patients but five completed the whole program and the minimal follow-up period was 24 months. At the end of irradiation, 121 patients achieved a total remission, but local recurrences occurred in 56%. Moreover, acute intolerance was considered as severe in 34% of G1 patients, and included extensive mucosal necrosis and bleeding. Although this rate was significantly reduced in G2 patients, late complications were observed in 20 of the 25 survivors, and included trismus, cervical sclerosis, and recurrent laryngeal edema. The crude survival rate is 13% at 2 years. Although this study was not randomized, this particular type of accelerated and hyperfractionated combination of irradiation did not really improve the clinical results in advanced carcinoma of the head and neck. Other schedules and probably other tumors, less extended, should be tested.

Sequential trial of initial chemotherapy for advanced cancer of the head and neck. DDP versus DDP + 5-fluorouracil.

The study, which compares DDP to DDP + FU, was planned to detect an increase by 60% in efficacy and by 5% in toxicity (2a = B = 5%) for DDP + FU. In a previous trial DDP produced 15% of responders and 5% of high-level toxic manifestations. The eligible patients with an advanced head and neck cancer were paired off successively on the basis of the tumour site and the UICC stage. DDP (100 mg/m2; day 1) was administered with hyperhydration, alone in the first protocol and followed by a 5-day continuous infusion of 5-FU (1 g/m2) in the second one. Courses were repeated every three weeks. Assessment was carried out after three courses or two, in cases of toxic manifestations. Seventy-four patients, who were paired off, entered the trial. The median age was 55 years and the median Karnofsky index was 90. The tumor site was as follows: 28 hypopharynx, 28 oropharynx, 8 oral cavity, and 10 multiple primary cancers. According to the UICC stage, there were 14 T1/T2 N3, 60 T3/T4 with among them 45 N3, and they were all MO. Comparisons were made through sequential closed plans. The combination chemotherapy was more efficacious than DDP with a difference that could be appreciated by the sequential analysis as high as 60% (95% confidence interval, 38% to 82%). The high-level toxicity appeared more significant (+25%) for the association. After radiation therapy 11 of 37 patients (30%) achieved a complete response in the arm with DDP versus 18 of 37 (49%) in that with DDP + FU. The median survival times were 9 and 11.5 months, respectively, and were not statistically different.