M. Henry-Amar

Pericarditis and myocardial infarctions after Hodgkin's disease therapy

From 1971 to 1984, 499 patients with all stages of Hodgkins disease received mediastinal irradiation at the Institut Gustave-Roussy by 25 MV photons from a linear accelerator. Thirty-five pericarditis (10-year cumulative incidence rate of 9.5%) and 13 myocardial infarctions (MI) (10-year cumulative incidence rate of 3.9%) were observed. In contrast, no cases were diagnosed in a parallel series of 138 Hodgkins disease patients treated without mediastinal irradiation during the same period of time (p less than 0.005 for pericarditis, p less than 0.05 for MI). By multivariate analysis, the role of total radiation dose given to the mediastinum and that of fraction size were evaluated, adjusting for age, sex, mediastinal involvement, and type of chemotherapy. The pericarditis risk was significantly increased with total dose greater than or equal to 41 Gy (relative risk (RR) = 3.25, p = 0.006) and with dose per fraction greater than or equal to 3.0 Gy (RR = 2.0, p = 0.06). The myocardial infarction risk was not found to be related to total dose nor to fraction size in this series, possibly because of the small number of events.

Prognostic factors in primary gastrointestinal non-Hodgkin's lymphoma. A multivariate analysis, report of 106 cases, and review of the literature.

The authors have reviewed 106 cases of primary gastrointestinal non‐Hodgkins lymphoma (GI‐NHL) treated at the Institut Gustave‐Roussy (IGR), France, between 1975 and 1986. The occurrence was 55 in the stomach, 26 in the small intestine, ten ileocecal, seven in the large intestine, and eight patients had multiple involvement. Patients were clinically staged according to the Ann Arbor staging system using the modification of Musshoff for Stage IIE. All histologic material of the 106 patients were reviewed and graded according to the Working Formulation (WF) and the Kiel classifications. Most patients received combination chemotherapy as part or all of their primary treatment program (95 patients, 90%). Seventy five patients (71%) had a multimodality treatment. The overall 5‐year survival rate was 60%. Sixteen variables were tested by univariate analyses for prognostic influence on survival. Of these, only clinical stage (P < 0.001), the achievement of initial complete remission (CR) (P < 0.001), erythrocyte sedimentation rate (ESR) (P = 0.01), mesenteric involvement (P = 0.03), and serosal infiltration (P = 0.05) were significant prognostic factors. Important variables were tested by a multivariate analysis using the Cox model taking into account different treatment modalities. Only three variables entered the regression analysis at a significant level: clinical stage (P = 0.02), surgical resection (P = 0.03), and histologic grade (Kiel) (P = 0.04). When the achievement of initial CR was introduced into the model, it was the most significant variable (P < 0.001) whereas all other variables became nonsignificant except for the histologic grade (Kiel) (P = 0.004). Based on results of the multivariate analyses we propose two prognostic classifications of patients: one at the initial evaluation depending on clinical stage, surgical resectability, and histologic grade (Kiel); the other at the end of primary treatment depending on the achievement or not of CR and the histologic grade.

A multivariate analysis of prognostic factors in early stage hodgkin's disease

A multivariate analysis of the prognostic factors was carried out with a Cox model on 1,139 patients with clinical Stage I + II Hodgkins disease included in three controlled clinical trials. The following indicators had been prospectively registered: age, sex, systemic symptoms, erythrocyte sedimentation rate (ESR), number and sites of involved lymph node areas, histologic type, clinical stage, pattern of presentation, results of staging laparotomy when performed, as well as the date and type of treatment. A linear logistic analysis showed that most of the indicators are interrelated. This emphasizes the necessity of a multivariate analysis in order to assess the independent influence of each of them. The two main prognostic indicators for relapse-free survival are systemic symptoms and/or ESR and number of involved areas. The only significant factor for survival after relapse is age. Sex has a small but significant influence on relapse-free survival. The relative influence of each indicator varies with the type of treatment and these variations may help in understanding the biologic significance of the indicators.

Prognostic significance of erythrocyte sedimentation rate in clinical stages I-II of Hodgkin's disease.

A prospective study was undertaken in 1963 on the respective prognostic significances of erythrocyte sedimentation rate (ESR) and presence or absence of systemic symptoms in Hodgkins disease. Six hundred seventy-six patients with clinical stages I or II were included in this study; 376 from 1963 to 1971 who were included in the H1 trial of the European Organization for Research and Treatment of Cancer (EORTC) and 300 who had been enrolled in the EORTC H2 trial from 1972 to 1976. All relevant data and long-term follow-up are available from 649 patients who were analyzed in this study. Multivariate analysis (Cox model) was carried out to assess the prognostic value of ESR independently of the other prognostic parameters and of the treatment. The results showed that of all the prognostic indicators studied, ESR is the one which has the highest correlation with relapse-free survival; however, initial ESR is not correlated with the probability of death after relapse. The presence or absence of systemic symptoms has less prognostic impact. Despite a close correlation between systemic symptoms and ESR, the two are not redundant and it is useful to combine both.

The EORTC trials for limited stage Hodgkin's disease

SINCE 1964, all the efforts of the Lymphoma Group of the EORTC (European Organisation for Research and Treatment of Cancer) have been devoted to the task of tailoring treatment to the presentation of Hodgkin’s disease (HD) for any given patient [l-12]. We will first briefly review the results of the four controlled studies conducted by the group from 1964 to 1988 for stages I and II HD. We will then present in detail the designs of the on-going H7 randomised trials for these same subsets of Hodgkin’s disease patients.

Late radiation injuries of the gastrointestinal tract in the H2 and H5 EORTC Hodgkin's disease trials: emphasis on the role of exploratory laparotomy and fractionation.

Out of 516 patients who entered in the two successive EORTC trials H2 and H5 for supra-diaphragmatic stages I and II Hodgkins 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)

Intensive systemic chemotherapy in localized Ewing's sarcoma in childhood. A historical trial

To assess the value in Ewings sarcoma of a new multiagent therapy (vincristine, cyclophosphamide, Adriamycin, (doxorubicin) procarbazine), 30 children with a localized tumor (eight distal, nine proximal, 13 central lesions) treated at the Institut Gustave‐Roussy between 1973 and 1976 (E3), were pairmatched by site of primary with 30 control patients treated without intensive chemotherapy between 1967 and 1972 (E1) at the same institution, both groups having the same local radiotherapy. Actuarial survival and disease‐free survival rates at six years were significantly higher in E3 at P < 0.01, respectively, 58% and 49% versus 25% in E1. The prognostic value of the primary site was ascertained only in children under chemotherapy. In this group there were six early relapses with death within 14 months and nine late relapses at 21 to 38 months. Among these nine patients, six died, one is living with disease, and two are currently alive in second remission. Fifteen patients are continuously free of disease 50 to 90 months after first treatment (median, 69 months): functional sequelae are minimal in six, moderate in seven, and severe in two children with limb amputation. It is concluded that in future treatments chemotherapy must be intensified and begun prior to local treatment which has to be reevaluated for radiation modalities and for radical surgery indication.

Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin's disease.

A retrospective study was undertaken at the Institut Gustave Roussy (IGR) to determine the predictive ability of changes in the erythrocyte sedimentation rate (ESR) during posttherapy periods for early relapse (within 18 months from start of therapy) and long-term survival in Hodgkins disease (HD). Three hundred one patients with clinical stages (CS) I or II HD entered in the European Organization for Research and Treatment of Cancer (EORTC) clinical trials were included in this study. All relevant data and long-term follow-up were available for these patients. A stepwise logistic regression was performed to assess the prognostic value of ESR changes independent of other prognostic parameters and treatment. The incidence of early relapse was found to be significantly increased in patients in whom ESR remained elevated (greater than 30 mm at one hour) after completion of therapy, regardless of the value before therapy. This was true whether the ESR was elevated in plateau fashion, oscillating between normal and abnormal, or was lower than at onset, but still abnormal. Moreover, early relapse predicted by elevated ESR posttherapy was associated with poor survival despite subsequent initiation of combination chemotherapy. Thus, the persistence of an abnormal ESR appears to be a reliable indicator for high probability of early relapse and subsequent poor prognosis. This might be introduced as a prognostic variable in the design of future therapy programs for HD.

Follow-up thallium-201 scintigraphy after mantle field radiotherapy for Hodgkin's disease.

PURPOSEnAssessment of the long-term cardiac effects of mediastinal radiotherapy for Hodgkins disease, by Thallium scintigraphy.nnnMETHODS AND MATERIALSn32 patients (14 males and 18 females) who underwent mantle field radiotherapy for Hodgkins disease were included in this study. Twenty patients received 4 fractions of 2.5 Gy per week and 12, five fraction of 2 Gy per week, delivered on alternate days. All the patients, except three, performed exercise testing electrocardiogram and Thallium-201 tomoscintigraphy. The average time interval from completion of treatment to the study was 7 years (range 3-13 years). No patients had clinical symptoms of cardiac disease. Mean age at the time of the study was 35 years (range 23-48 years).nnnRESULTSnTwo electrocardiograms revealed left bundle branch block and the patients were excluded from the study. Only one out of 27 exercise electrocardiograms was abnormal in a patient with mitral valve prolapse, who was also excluded from the study. Twenty-six scintigraphies were evaluable. Twenty-two (85%) were clearly abnormal with partial or complete redistribution on delayed images. The anterior region was affected in 19 of these cases (86%). Four explorations were undoubtedly normal. Coronary angiography was not performed for ethical reasons in these asymptomatic patients.nnnCONCLUSIONnDespite possible false positive tests, the high rate of abnormality (85%) in this small series is striking. These preliminary data justify larger studies and a close long-term follow-up of these patients.

Secondary solid malignant tumors occurring after bone marrow transplantation for severe aplastic anemia given thoraco-abdominal irradiation

PURPOSEnWe 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.nnnRESULTSnAll 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.nnnCONCLUSIONnTumors 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.