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Purpose: Prospective investigation of spontaneous and in vitro radiation-induced apoptosis to predict early response to palliative radiotherapy in patients with non-Hodgkin's lymphomas., Patients and Methods: Fine-needle sampling was performed in 28 tumor sites (26 patients) and yielded adequate cell numbers in 27 cases. Apoptotic cells were counted by fluorescence microscopy immediately after sampling and after 24-h culture (spontaneous apoptosis) and 24 h after 2- and 10-Gy in vitro irradiation (radiation-induced apoptosis). Early response to low-dose in vivo radiotherapy (mostly 4 Gy in two fractions over 3 days) was evaluated 15 days after treatment., Results: The tumor response rates at 15 days were 11 (39%) complete responses, nine (32%) responses of greater than 50% reduction in volume, six (21%) responses of less than 50% reduction in volume and two (7%) cases of no response. Tumors achieving complete or major response after in vivo irradiation had higher percentages of apoptotic cells after in vitro irradiation, while no significant differences in terms of spontaneous apoptosis were observed between responders and non-responders., Conclusion: Spontaneous and in vitro radiation-induced apoptosis can be easily and quickly assessed on cells obtained by fine-needle sampling of non-Hodgkin's lymphoma lesions. The present results suggest that in vitro radiation-induced apoptosis could be used as a predictive assay of early response to low-dose in vivo irradiation in patients with non-Hodgkin's lymphomas.

Purpose: to estimate the alpha/beta ratio for damage to human lung after thoracic irradiation for Hodgkin's disease., Patients and Methods: The criterion for lung injury was the presence of radiological changes in the vicinity of the mediastinum as assessed on regular follow-up chest X-ray examinations. Patients with supradiaphragmatic stage I-II Hodgkin's disease received mantle field irradiation as part of their treatment between 1964 and 1981 (E.O.R.T.C. protocols H1, H2, and H5). The total mediastinal doses fixed by the protocols were 35-40 Gy. The fractional doses were left to the decision of the physicians in charge: the most frequent regimens were 5 x 1.8, 5 x 2.0, 4 x 2.5 and 3 x 3.3 Gy per week. The data were fit to the linear-quadratic (L.Q.) model using time-to-injury as endpoint., Results: 1048 (97%) of 1082 patients were evaluable. The mean follow-up duration was 8 years. One hundred and ninety-five cases of radiologically-visible lung damage were observed after a median interval of 6 months (range: 0-101). The 3-year actuarial probability of lung damage was 19% (95% confidence limits: 17, 21). Multivariate analysis (Cox model, stratified by protocol) showed an increased risk of damage with dose per fraction (relative risk, R.R. = 2.22 per Gy (1.75, 2.82)), the presence of systemic symptoms (R.R. = 1.53 (1.09, 2.15)), and total mediastinal dose (R.R. = 1.06 per Gy (1.01, 1.12)). Age, sex, histological type, number of involved nodal sites and radiotherapy duration did not significantly modify the risk of lung damage. The L.Q. model parameters were: alpha = 0.031 Gy-1 (0.003, 0.059), beta = 0.010 Gy-2 (0.007, 0.013), alpha/beta = 3.07 Gy (-0.23, 8.46)., Conclusion: this low alpha/beta ratio is consistent with late effects values from animals and humans, and illustrates the influence of large fraction sizes on the occurrence of late pulmonary complications.

Purpose: We have evaluated irradiation doses received at location of secondary solid tumors occurring after bone marrow transplantation (BMT) in five of 147 patients grafted for severe aplastic anaemia., Results: All 5 tumors occurred within the radiation field penumbra. The estimated received dose varied from 6 Gy for one inner field secondary tumor, to 2.5 Gy for the remaining secondary tumors., Conclusion: Tumors may arise in the zone where the delivered radiation dose drops dramatically. Irradiation, with associated cofactors, may promote the development of epidermoid carcinoma in irradiated patients for BMT.

Accuracy of patient positioning and dose delivery in mantle field irradiations was investigated on 29 patients treated between August 1990 and December 1991. Patients were treated in two different centers, University Hospital St. Rafaël in Leuven and Institut Gustave Roussy in Villejuif, where different techniques and procedures were used. Measurements were performed on 341 portal films and entrance doses were measured in 518 treatment set-ups. The impact of systematic errors occurring during treatment preparation and day-to-day variations on the accuracy of treatment execution were separately analysed. Daily reproducibility, defined as the deviation from the respective mean measured value for a treatment was demonstrated to be good for both the treated volume and the delivered dose and no difference between the two techniques was shown. Comparing the successive portal films of individual patients (reproducibility of a treatment, once it has started), only small day-to-day variations are found: the SD is 3.4 mm for craniocaudal movements and 2.6 mm for lateral movements. For dose delivery very narrow distributions are obtained with SDs of, respectively, 1.5% and 1.85% for the Leuven and the Villejuif group. This suggests that the position of the patient, which is often thought as the critical point in this complex set-up can be done in a very accurate way, regardless of the position used. To assess the global accuracy of the treatment, the actually treated volume and delivered dose were compared with the planned values. Apart from reproducibility this also takes into account the whole preparatory procedure between planning and the start of the therapy (first session).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum alpha-amylase was measured before and 24 h after either total body (31 patients) or localized irradiation including the salivary glands (40 patients) or the pancreatic area (22 patients). A significant increase in amylasemia was observed for doses to the parotid glands larger than 0.5 Gy. A sigmoid function of dose was fitted to the data and predicted a maximum amylasemia level for doses larger than 4 Gy and smaller than 10 Gy. The raw data from other published series were adequately described by the same model. However, the confidence limits of the parameters remained wide, because of a considerable interindividual variability. Post-irradiation hyperamylasemia appears to provide a good criterion for triage of accidentally irradiated patients: 24 h after a dose larger than 2 Gy to the parotid glands, 91% of the patients had an amylasemia level higher than 2.5-fold the upper normal value (sensitivity). Conversely, 96% had their serum amylasemia lower than 2.5-fold the upper normal value when dose was smaller than 2 Gy (specificity). However, a retrospective estimation of the absorbed dose (dosimetry) is not likely to be very precise because of the large interindividual variability.

In 1991, the vast majority of radiotherapy centers are implemented with computer treatment planning systems (TPS), and it has become routine practice to compute full absorbed dose distribution (ADD) in almost all treatment situations. Usually the target is covered by the 100% isodose and the surrounding normal tissues receive a lesser dose than the tumor. It implies, that, as the dose per fraction of, say, 2 Gy is prescribed at the 100%, normal tissues receive a daily dose different than 2 Gy. The absorbed doses delivered at different organs have therefore not the same biological effectiveness and must be corrected according to the actual dose per fraction for a proper interpretation of the treatment planning. This is of great importance since most of the "tolerance levels" used in the practice have been determined for doses per fraction around 1.8-2 Gy. The linear-quadratic (LQ) model provides a simple method for establishing biological equivalencies and has been used throughout this article to establish the difference between the absorbed dose computed by the TPS and its biological equivalent. It is shown that normal tissues receiving less than 100% of the daily dose are relatively more protected than suggested by the ADD, and, inversely, that normal structures overdosed and thus receiving more than the 100% daily dose are relatively more at risk for complications than suggested from the ADD.

In 1980, based on experimental and clinical data, a protocol was developed at the Institut Gustave-Roussy (IGR), alternating eight monthly courses of chemotherapy (CHVP) and two, then three, radiotherapy sequences (15 Gy in 6 fractions and 10 days to the initially involved areas), for early stage unfavourable histology non-Hodgkin lymphomas (NHL). The results are updated for 55 selected patients presenting with bulky stage I and II NHL, intermediate and high grade according to the Working Formulation. Five-year overall survival rate was 69% and freedom from progression was 68%. Early haematologic and digestive tolerance was satisfactory, probably because a 10-15-day interval was respected between chemotherapy and radiotherapy and vice versa. No late toxicity was detected in 39 patients who presented with head and neck localizations; xerostomia was found to be only mild and transient. All patients given mediastinal irradiation experienced radiological mediastinitis, but functional impairment was usually moderate. One of the 4 patients who received 3 x 15 Gy radiotherapy courses to part of the abdomen, died of small bowel obstruction and perforation. The study demonstrated the feasibility of an alternated schedule of chemotherapy and radiotherapy, with satisfactory results in terms of long-term survival. However, the few late complications which were detected after irradiation of the abdomen or of the thorax led to an alteration of the initial scheme when these volumes are to be treated.

Most available clinical data strongly suggest a sparing effect of TBI fractionation for the lungs, liver, lens, the growth cartilage and, perhaps the prepubertal ovary; the usual fractionated TBI regimens, delivering from 12 to 15 Gy, appear to be constantly less toxic than the "standard" 10 Gy single dose TBI scheme. However, there is also some clinical suggestion, essentially coming from the T-depleted graft experience, that the largely used 12 Gy fractionated scheme (6 X 2 Gy) might be less effective than the standard 10 Gy single dose TBI for leukemia cell killing and for eradication of the recipient bone marrow. Additional clinical data, ideally coming from well designed randomised trial or from careful large-scale retrospective evaluations, should help to optimize the TBI delivery.

Out of 516 patients who entered in the two successive EORTC trials H2 and H5 for supra-diaphragmatic stages I and II Hodgkin's disease (HD), and who received an infra-diaphragmatic irradiation, 36 (7%) developed late radiation injuries of the gastrointestinal tract (GIT). Twenty-five patients presented with ulcers (stomach or duodenum), 2 with severe gastritis, 6 with small bowel obstruction or perforation and 3 patients had both an ulcer and bowel obstruction. A previous laparotomy played an important role. While the complication rate was 2.7% without any previous abdominal surgery, it was 11.5% after laparotomy (p less than 0.001). Fractionation was also found to be of importance in the occurrence of complications: three different weekly schedules were used -5 x 2 Gy, 4 x 2.5 Gy and 3 x 3.3 Gy; the GIT complication rates were 4, 9 and 22%, respectively (p less than 0.001). When combining laparotomy and fractionation, we found that the patients who were treated using 5 weekly fractions of 2 Gy without any prior laparotomy had a very low rate of late digestive complications (1%), whereas the patients who received 3 weekly fractions of 3.3 Gy after laparotomy presented a 39% complication rate. The other subgroups of patients were at an intermediate risk (from 5 to 13%) of late digestive injuries. Since most patients received 40 Gy with only very small variations, the influence of the radiation dose could not be investigated.(ABSTRACT TRUNCATED AT 250 WORDS)

The early response of blood cells to irradiation has been studied in leukemia patients who received total body irradiation (TBI) prior to cyclophosphamide and bone marrow transplantation. After a single session treatment (10 Gy in 4 h) the most dramatic variation was observed in the granulocytes. At the end of the irradiation their concentration was 2 to 6 times higher. Because of a subsequent rapid decline, the peak may be overlooked if the blood counts are delayed. Lymphocytes decreased to 50% at the end of the single session TBI and continue to decrease exponentially, with a half time of 30 h. During a fractionated irradiation (11 X 1.2 Gy in 4 days) the lymphocyte number dropped to 60%, 13 h after the first fraction and this decline continued with a half time of 30 h during the treatment. From the data obtained in vivo, a lymphocyte D0 value of 1.2 Gy was computed. The lymphocyte subsets (B.T. OKT4 OKT8) did not exhibit different radiosensitivities either in vivo or in vitro. The disappearance of lethally hit lymphocytes from the blood exhibits a biphasic kinetic: 50% of the cells disappear in a few hours and 50% with a half time at 30 h. Lymphocytes irradiated either in vitro or in vivo when in culture disappear slowly, contrasting with the in vivo findings. It may suggest that lethally hit lymphocytes are quickly removed from the circulating pool in vivo.

In 1980, on the basis of fundamental and clinical data, a protocol was developed at the Institut Gustave-Roussy, alternating eight monthly courses of chemotherapy (CHVP) and two or three radiotherapy sequences (15 Gy in 6 fractions of 10 days, each), to treat non-Hodgkin's lymphomas of unfavourable histologies, mainly stage II, presenting bulky tumours. Systemic, haematological and digestive tolerances were satisfactory. For 19 previously untreated stage II patients, overall survival and relapse-free survival after 30 months were 85 and 65%, respectively. Three of the relapses were observed in patients who did not receive the alternating schedule in an optimal way; this suggests that these results can be further improved.

Patients with stage I and II non-Hodgkin's lymphoma (NHL) are considered to have a relatively good prognosis. For this reason, they are seldom referred to specialized centers and the accrual of such patients in controlled studies is limited. Therefore, significant studies of homogeneously treated patients are difficult to collect and the management of these patients remains controversial. Some patients do very well after treatments with minimal toxicity while others require a much more aggressive approach. The Radiotherapy-Chemotherapy Group of the EORTC carried out its second controlled trial on patients with stage I and II NHL from 1975 to 1980. Its first aim was to assess the prognostic value of histologic classifications independently of treatment. The second aim was to compare two therapeutic options within each stage. In stage I, 124 patients were randomized to receive extended field radiotherapy (RT) either with or without adjuvant cyclophosphamide, vincristine prednisone (CVP) chemotherapy (CT). Relapse-free survival (RFS) was higher in patients who received adjuvant CVP but the total survival rates were not different. The RFS was lower in patients with diffuse than in those with follicular architectural histologies; in the former, RFS was not influenced by adjuvant CVP. Those patients who underwent a staging laparotomy had a higher 5-year total survival (TS) independent of the histologic type. Fifty-six stage II patients were included and extended field was randomized versus total nodal irradiation. Subsequently, adjuvant CVP was given to all patients. Results are good in follicular histologies but the advantage for total nodal irradiation is not significant. In diffuse histologies, results were unsatisfactory in both arms; a new therapeutic strategy was designed in which RT and CT are alternated and has been successfully tested in a pilot study.

Out of 134 patients irradiated below the diaphragm to a dose of 40 Gy for Hodgkin's disease at the Institut Gustave-Roussy, 19 (14%) were subsequently found to present with radiation injuries of the gastrointestinal tract. Since five patients presented with two different injuries, 24 radiolesions were observed. Most of them (17 out of 24) were gastric or duodenal. Twelve (out of 24) were ulcers. Nine patients required surgery. A complete cure of the radiation injuries was obtained in 15 out of 19 patients. Sex, age, stage, histology or initial chemotherapy were not found to play a role in the occurrence of radiation damage. On the contrary, the role of a previous exploratory laparotomy appeared important; for the patients who underwent laparotomy and irradiation, the complication rate was 23%. For the patients treated by irradiation alone, the complication rate was 7% (p less than 0.01). Fractionation was found to be another important parameter: for 52 patients treated using 3 weekly fractions of 3.3 Gy, the complication rate was 25%, compared to 8% (p less than 0.01) for 76 patients treated using 4 weekly fractions of 2.5 Gy. Combining these two factors, we found a 42% complication rate for the group of patients who underwent laparotomy and who were treated by means of 3 fractions of 3.3 Gy per week, whereas patients irradiated using 4 weekly fractions of 2.5 Gy, without any previous laparotomy, had only a 5% complication risk (p less than 0.001).

The few clinical studies which have utilized irradiation as a treatment modality for chronic lymphocytic leukaemia (CLL) during the last two decades have led to rather conflicting and sometimes disappointing results. Low-dose total body irradiation (TBI) and extracorporeal, or mediastinal, radiotherapy did not appear to be superior to chemotherapy in most trials. Only the fractionated low-dose (600-800 rad) splenic irradiation was found to induce a long-lasting decrease of the lymphocyte count and a decrease in bone marrow infiltration in a significant proportion of cases, without any noticeable haematological toxicity. But new data is recently emerging; stratification of CLL in various subgroups, better understanding of the role of the normal T-cell subsets, better knowledge of the interaction between irradiation and haematopoiesis, and of the radiosensitivity of the various lymphocyte subpopulations. Thus one can now reconsider the possible role radiotherapy, and particularly splenic irradiation, can play as an alternative treatment to chemotherapy for CLL. Haematological toxicity is still limiting the use of TBI. The spleen irradiation avoids this drawback. Recent data suggest that this splenic irradiation could be efficient by means of several mechanisms; the successive destruction, fraction after fraction, of the part of the malignant lymphocyte clone present in the spleen is likely to be the main therapeutic explanation, with the knowledge that the lower the differentiation of the malignant clone, the more efficacious the irradiation. But in parallel, the destruction of the large subset of T-suppressors which is constantly present in the spleen may account for the improvement of the peripheral blood count after splenic irradiation, and possibly for a direct effect towards the malignant clone. With respect to these new data, splenic irradiation clearly needs further clinical evaluation in the treatment of CLL.

Sequential thoracic CT-scanning was performed for 14 patients presenting with residual mediastinal masses on chest X-ray after treatment of stage I and II Hodgkin's disease (HD). Eleven patients initially presented with bulky mediastinal involvement. No mediastinal biopsy was performed. No local recurrence was detected at a 48 month median follow-up. Early evaluation by CT-scanning showed cystic degeneration in three cases. Sequential CT-scans on longer follow-up demonstrated continuous regression of residual masses in six cases and no or limited volume reduction in six other cases. In two patients, part of the residual mass remained stable and the other part showed reduction in size. In addition, late calcifications developed in four cases. The results of sequential CT-scanning suggest that residual mediastinal masses do not generally represent active disease. Hence additional, potentially toxic, therapy can be avoided.

At the Institut Gustave-Roussy (IGR), from January 1982 to December 1986, 54 patients received total body irradiation (TBI) as a part of the conditioning regimen before allogeneic bone marrow transplantation. The patients were non-randomly assigned to either single dose TBI (STBI) (31 patients receiving 10 Gy at a 4.5 cGy/min dose rate, 8 Gy to the lungs) or to a hyperfractionated scheme (HTBI) (23 patients receiving 13.2 Gy in 11 fractions, 3 fractions per day, 9 Gy to the lungs). Relapse rate and overall survival were not significantly different in the two STBI and HTBI groups, in spite of a larger number of 2nd and 3rd remission patients in the HTBI subset. The incidence of interstitial pneumonitis (IP) was significantly reduced in the HTBI group (13%, versus 45% after STBI, p = 0.02). Lethality by IP was also lower after HTBI (4%, versus 26% after STBI, p = 0.08). There was no case of veno-occlusive disease of the liver in the HTBI group, whereas three cases were observed after STBI. Based on these results, the IGR activated, in January 1987, a randomized trial comparing the single dose 10 Gy TBI (8 Gy to the lung) to a new hyperfractionated schedule (11 fractions of 1.35 Gy, 3 fractions per day, 9 Gy to the lungs).