Search

From 1964 to 1987, the EORTC Lymphoma Group conducted four consecutive controlled clinical trials on clinical stages I and II Hodgkin's disease in which 1,579 patients were entered. From the onset the main aim of these trials was to identify the subsets of patients who could be treated safely by regional radiotherapy (RT). Therefore, several prognostic indicators were prospectively registered and progressively used in the trial protocols for the delineation of the favorable and unfavorable subgroups as soon as they were recognized of high predictive value. In the H2 trial (1972 to 1976), the histologic subtype was the only variable taken into account for the therapeutic strategy and the staging laparotomy findings were found to be of prognostic value only in patients with favorable prognostic indicators. In the H5 trial (1977 to 1982), patients were subdivided into two subgroups according to six prognostic indicators. Patients with favorable features were submitted to a staging laparotomy (lap); lap negative patients were randomized between mantle field RT and mantle field plus paraaortic RT. Disease free survival (DFS) and total survival (S) were similar in the two arms. Among patients with unfavorable features, DFS and S were significantly higher in the arm treated by combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) chemotherapy (CT) and RT than in the arm treated by total nodal irradiation. Nevertheless, in patients below the age of 40, the overall survival rates were equivalent in the two arms. In the H6 trial, the delineation of the favorable subgroup was based on (a) absence of systemic symptoms and elevated ESR, (b) no more than one or two lymph node areas involved. The aim of the study was to assess the impact on survival of a therapeutic strategy including staging laparotomy. At a 4-year follow-up, no difference in survival was evidenced. In patients with unfavorable prognostic indicators, 3 MOPP- RT-3 MOPP were compared with 3 ABVD-RT-3 ABVD. From H1 to H5 trials, the proportion of patients having received CT during the course of the disease gradually decreased; the data suggest that a further reduction in the proportion of patients aggressively treated is conceptually possible. On the basis of the prognostic factors identified, one can delineate three subsets of patients and modulate toxic cost of the initial treatment according to the characteristics of these subsets. In the most favorable subgroup, RT alone produces high survival and CT is not justified.(ABSTRACT TRUNCATED AT 400 WORDS)

The natural history of human cancers can be simulated assuming an exponential growth pattern. This simple model shows that the duration of the tumor growth during the occult phase is always much shorter than the interval between the carcinogenic stimulus and the clinical emergence of the tumor; this is consistent with the existence of several stages of precancerous lesions which precede the development of the neoplastic clone. Metastatic spread can be simulated and a model of tumor growth can be used to predict the proportion of patients in whom metastatic dissemination can be avoided by an earlier diagnosis. The model predicts also that in the subsets of patients in whom metastatic spread occurs early the occult metastases will be large at the time of the treatment of the primary tumor and therefore adjuvant chemotherapy (CT) will be less effective; this is in keeping with clinical data. The model can also help to understand the relationship between the local control of a tumor and the cure of the patient, and to explain the discrepancy between the great reduction in the local incidence of local recurrence obtained with post-operative radiotherapy and its relatively small impact on survival. However, this simple model is insufficient to explain several features of the course of a human cancer, in particular the heterogeneity of the neoplastic cell population and the inexorable tendency for some cancers to progress towards a more malignant type and to become progressively more resistant to any treatment. Genetic instability appears to be an essential characteristic of human cancers and variations in its degree may be the cause of differences in the aggressiveness and in the severity of the various types of cancers. The recent advances in the molecular biology of cancers has already given to clinicians new and powerful prognostic indicators. These will probably, in the near future help, towards a better understanding of the biology of tumor growth and tumor progression.

Kinetic parameters of 99mTc and 131I thyroid trapping were compared in 13 patients (30 dynamic studies). The data were analyzed with a six-compartment model including three compartments for extrathyroid spaces. There was a good correlation between the estimates of the total iodide and pertechnetate pools (V4+V5). As expected, the ?14 loss rate constant for technetium was always higher than that for iodide.

The distribution of iodotyrosines and iodothyronines has been studied in poorly iodinated 19 S thyroglobulins isolated by sucrose gradient centrifugation from five human thyroid tissue. The 19 S thyroglobulins have been fractionated by isopycnic centrifugation in 34.5 % rubidium chloride gradient. The distribution of iodoamino acids depends on the total iodine content of each fraction. The variations in MIT1)and DIT residues with increasing levels of iodination are not identical, the elevation of DIT residues being higher than that of MIT. The number of T4residues increases quite rapidly after 5 atoms of iodine while T3increases slightly and slowly. It is shown here that, even after fractionation of poorly iodinated thyroglobulin, the synthesis of thyroid hormones is observed at a level of iodine content as low as 1.4 and 1.8 atoms per molecule of thyroglobulin. This shows that the thyroglobulin fractions obtained by isopycnic centrifugation are still heterogeneous, although less than the initial non-fractionated thyroglobulin. In order to explain our data, it must be admitted that a large proportion of thyroglobulin molecules are not iodinated.

The usefulness of serum thyroglobulin (Tg) assay in the follow-up of differentiated thyroid carcinomas has been evaluated in 109 subjects divided into two groups.Group 1 included 64 patients who had undergone total thyroid ablation. In 40 of the 41 patients in complete remission serum Tg was undetectable during replacement therapy (TSH below 5 μU/ml). In 18 out of the 40 patients serum TG was detectable following endogenous TSH stimulation. As 83% of these patients had ectopic uptake prior to the last radioiodine treatment, this release of Tg under TSH stimulation suggests the persistence of occult neoplastic tissue. Of the other 23 patients, 20 had bone or lung metastases and 3 patients had lymph node recurrences: in all these patients, serum Tg was detectable during replacement therapy and increased after TSH stimulation.Group 2 included 45 patients in whom normal residual thyroid tissue was present at the time of the investigation. Of these, 35 patients were in apparent remission and 19 of them had detectable Tg level within the normal range. The other 10 patients had detectable metastases and in 4 of these the Tg level was also within the normal range. Thus, no conclusion can be drawn from a normal Tg level in the presence of residual thyroid tissue. Bovine TSH stimulation did not improve significantly the diagnostic value of Tg assay in this group of patients.

Between 1943 and 1965, 359 patients with carcinoma of the thyroid were treated by external radiotherapy or radioiodine out of a total number of 560 patients treated during the same period.In 65 of these patients surgery had been satisfactory from a macroscopic point of view. Prophylactic post-operative irradiation was given to 55 and the survival rate was 91 per cent at five years and 85 per cent at ten years. Ten received radioiodine, eight were alive at five years and six at ten years.In 95 patients excision of the tumour had been macroscopically incomplete. Fifty-four were treated by external radiotherapy and the survival rates were 50 per cent at five years and 48 per cent at ten years. For the differentiated carcinoma of this group 68 per cent were surviving at five years and 58 per cent at ten years. Of 41 patients treated with radioiodine, 75 per cent were surviving at five years and 31 per cent at ten years.Eighty-five patients were inoperable. Sixty were treated by external radiotherapy, the survival rates were 17 per cent at five years and 8·5 per cent at ten years. For the differentiated carcinomas of this group the survival rates were 24 per cent and 18 per cent. Twenty-five were treated with radioiodine, 26 per cent were surviving at five years and 4·5 per cent at ten years.The patients treated by external radiotherapy can be divided into two subgroups according to the technique of treatment and dose used. Between 1943 and 1955, patients were treated with conventional X rays (mean applied dose 2,800 rads), between 1956 and 1965 the patients were treated with 60Co (mean applied dose 5,000 rads). For the 45 patients of the first group, the survival rates were 35 per cent at five years and 32 per cent at ten years. For the 124 of the second group the respective survival rates were significantly higher: 60·6 per cent and 53 per cent. The results of external radiotherapy were similar to those of radioiodine at five years and better at ten years.In conclusion, a dose of 5,000 to 6,000 rads delivered by megavoltage external radiotherapy in five to six weeks, is well tolerated and effective mostly in differentiated carcinomas and medullary carcinomas.The survival rates of 64 patients whose metastases were unable to pick up iodine is practically zero at five years. For 68 patients with uptake in their metastases the survival rates were 53 per cent at five years and 23 per cent at ten years. The survival rate in patients with pulmonary metastases was higher than in patients with bony metastases (75 per cent versus 44 per cent at five years and 42 per cent versus 8 per cent at ten years).

The authors have studied the consequences of irradiation of the upper part of the left kidney during treatment of the spleen. Seventy-four patients with lymphoma were entered in the study. They have all been followed up for between three and five years. Renal function was assessed by physical examination, biological tests, intravenous pyelograms and nephrotomographies, isotope scans with 197Hg neohydrin, dynamic studies with 131I hippuran and 99TcmDTPA. No significant changes have been noted for blood pressure, biological tests or IVP. Eighteen months after irradiation renal tomograms showed cortical atrophy of the superior pole of the left kidney. 197Hg neohydrin started to show reduced uptake of the isotope in the irradiated region of the left kidney by the eighth month. 131I hippuran and 99TcmDTPA detected abnormalities respectively five and three months after irradiation. No compensatory hypertrophy nor change in the overall kidney function have been noted.In Hodgkin's disease, radiotherapy has proved its efficiency in splenic involvement and the lack of secondary renal side effects. On the other hand, morbidity was shown to occur in 5% of cases after splenectomy. From these data, it is proposed to prefer radiotherapy rather than surgery for splenic treatment.

A patient suffering from acute lymphoblastic leukemia in the third progressive phase, refractory to the majority of available treatments, was given total-body irradiation of 800 r. dosage, after administration of methyl-nitro-imidazolyl-mercaptopurine (300 mg. daily for 4 days). One week after irradiation, he received an infusion of a mixture of equal parts of bone marrow from six donors (mother, sister, father and three brothers), a total of 5.8 x 1010 nucleated cells. Myeloid restoration began 2 weeks after the infusion and continued to progress rapidly. The reality of the graft was demonstrated by study of the erythrocytic antigens. Nearly all the erythrocytes found in the blood after 6 months belonged to the phenotype of one of the male donors. Studies of chromosomes and leukocyte sex chromatin suggested that a small proportion of leukocytes were being produced by the cells of one of the female donors. The patient was found to produce beta 2A, beta 2M and gamma globulins of the Inv type of the donors, suggesting that lymphoid cells may also have been successfully grafted. A skin graft from the male donor whose marrow graft had apparently been accepted was still perfectly intact 7 months after grafting, whereas the grafts from other donors were rejected, indicating a specific tolerance to tissues from this donor. Previous studies of compatibility between the recipient and the various donors by a histocompatibility test described by us, or by means of similarities in leukocyte antigens, indicated that the accepted donor had been antigenically more nearly compatible than the others. What appeared to be a secondary syndrome became manifest 1 week after marrow transfusion; it consisted of weight loss, digestive disorders (anorexia, nausea, vomiting, diarrhea), hepatic disturbances (hepatomegaly, increased serum concentrations of various enzymes), transient polyadenopathy (histologically composed of histiocytic proliferation and lymphocytic aplasia), desquamative erythrodermia, eosinophilia exceeding 50 per cent, and superinfection (including a probable miliary tuberculosis). The syndrome was controlled by careful symptomatic treatment; its intensity gradually abated. Reactivation of the secondary syndrome was accomplished by reinjection of leukocytes from the donor whose graft had been tolerated. This was controlled by Δ-1-cortisone and symptomatic treatment. The patient was still alive and in apparently complete hematologic remission from the leukemia 12 months after the treatment described above. Particular reasons for this success possibly include the absence of previous blood transfusions and the use of multiple marrow donors.

Three hundred and three patients with polycythemia vera have been treated with 32P more than five years ago. Seven patients have been excluded because they have been treated by 32P elsewhere before their first visit. Of the 296 other patients, 269 have been followed up regularly for more than 5 years. The median survival after hematologic diagnosis is 14.5 years. It is shorter in older patients and in those patients who had the shortest remissions after the initial 32P treatment. Of 145 patients who had died, death was due in 53 cases to hematologic complications (29 acute leukemia, 4 chronic leukemia, 16 myeloid metaplasia or myelofibrosis, 4 aplastic anemia). The latter complications were seen most commonly in those patients who had received the highest total dose of 32P, those with a high initial white count and those in whom the spleen was palpable at least 2 cm. beneath the costal margin. The influence of the quantity of 32P given is very significant for equivalent clinical situations, the influence of white cell count and spleen size is significant for equal doses of 32P. This suggests that these two types of factors favor the early occurrence of hematologic complications.

The radiosensitivity of a cell varies throughout the cell cycle, and the effects of a course of radiotherapy depend therefore on the distribution of the proliferating cells into the various phases of the cell cycle and on the proportion and characteristics of the quiescent cells. This is true not only of the first dose of radiation, but also applies when the subsequent doses are delivered.The difference in cell cycle durations between normal and malignant tissues and between different experimental and human tumour types is relatively small. It cannot be evoked to explain the wide range of tumour doubling times, which seems largely to be due to differences in the proportions of proliferating cells (growth fraction) and rates of cell loss.The slowing down of the growth rate of a solid tumour depends on these two parameters. In solid tumours, these parameters may vary from the centre of the tumour to its periphery and appear to be influenced by environmental factors.At least four types of factors can influence the growth rate of a tumour: immune reactions against tumour cells, metabolic conditions, cell crowding and specific inhibitors or stimulators.Various types of quiescent non-cycling cells may exhibit differences in radiosensitivity and repair capacity after sublethal damage.Irradiation or cytotoxic drugs produce a disturbance of the kinetics of tumour cell proliferation. An acceleration of the growth rate of surviving tumour cells has been observed both in man and in the experimental animal.This may be due either to depopulation which in itself increases the availability of nutrients or to the liberation of growth stimulating substances by necrotic cells.This repopulating ability of some tumours during a fractionated course of radiotherapy may be a reason for local failure. A better understanding of this phenomenon may help in the choice of the optimum type of fractionation.

The radiosensitivity of C3H mouse bone-marrow was measured at various times, after a conditioning dose of 250 R by a modified method of McCulloch and Till.There was a significant variation in radiosensitivity which is explained by partial synchrony of cells after the first dose of irradiation.The validity of the specific activity measurements of bone-marrow DNA as a test for synchrony is discussed.

Two groups of patients with thoracic oesophageal cancer were treated with a 22 MeV betatron. 54 patients received a dose of 6,900 rads in six weeks within the whole of the thoracic oesophagus. The average survival was 10·9 months and two patients were living five years after treatment. 61 patients received 5,200 rads within the whole of the thoracic oesophagus, and for these patients with a cancer of a length less than a fourth of the whole oesophagus, a complement of 3,500 rads to the tumour residue. The average survival was 11·4 months; one patient was living five years after treatment.