The EORTC trials for limited stage Hodgkin's disease. The EORTC Lymphoma Cooperative Group.
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Publications and source records attributed to M Henry-Amar.
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Twenty institutions/cooperative groups tabulated second cancers among 12,411 patients diagnosed with Hodgkin's disease between 1960 and 1987, giving 82,850 person-years of observation. Overall, 631 second cancers were observed, as compared with 223.25 expected (observed (O) to expected (E) ratio 2.83, p < 0.001) at least one year after the diagnosis of Hodgkin's disease. Second cancers were acute leukaemias (AL) in 158 cases as compared with 5.75 expected (O/E = 27.48, p < 0.001), non-Hodgkin's lymphomas (NHL) in 106 cases as compared with 3.34 expected (O/E = 31.77, p < 0.001), and solid tumors (ST) in 367 cases as compared with 214.16 expected (O/E = 1.71, p < 0.001), with no differences between males and females. Excess of ST was observed for the following anatomic sites: salivary gland, small intestine, colon, bronchus, pleura, bone, skin other than melanoma and thyroid in males; salivary gland, bronchus, pleura, skin other than melanoma and breast in females. While the excess of second AL and NHL was significant over the 1-14 year period after the start of initial therapy, that of second ST became apparent after the fifth year, increasing with time. Overall, the 15-year cumulative incidence rate of second cancer was 11.2%. It was 2.2%, 1.8% and 7.5% for second AL, NHL and ST, respectively. While the cumulative incidence of AL and NHL plateaued after 17 years, that of ST was still increasing. To analyse whether a particular treatment category was associated with an increased risk of second cancer, a prognostic study was performed on the 11,241 patients who achieved a complete remission and were continuously disease-free. Overall, 87 patients developed an AL, 68 a NHL, and 231 a ST. Combined modality treatments including MOPP or MOPP-like chemotherapy were associated with the higher risk of second AL (Relative risk (RR) = 17.11; p < 0.001) followed by age above 50 (RR > 4.50; p < 0.001), advanced clinical stage (RR > 2.50; p < 0.001), splenectomy (RR = 1.65; p < 0.05) and MOPP or MOPP-like chemotherapy used alone (RR = 2.20; p < 0.05). Factors associated with an increased risk of second NHL were age above 30 (RR > 3.5; p < 0.001), male gender (RR = 1.82; p < 0.05) and clinical stage III (RR = 1.70; p < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
In an effort to better determine the outcome of patients treated for Hodgkin's disease, twenty institutions/cooperative groups in the western world agreed in 1988 to participate in the development of a large data base by sending data to be analyzed by a common statistical design. Data was obtained from both patients randomized on prospective trials and patients treated by standard protocol but not randomized. Overall statistics on 14,315 adult patients treated from the early 1960s to 1987 were collected. This data was first presented at the Paris International Workshop and Symposium held on June 28-30, 1989. The proceedings, published in 1990, include a detailed description of the data, and prognostic studies on laparotomy findings, response to initial therapy, relapse-free survival, overall survival, and secondary malignancies. The International Database on Hodgkin's Disease represents a compromise between two more classical approaches such as the use of randomized trials and metaanalyses. It should serve as a model for the study of other types of cancer. It has been successful because of interest, time, and the cooperation of physicians in academic centers from much of the western world.
Fifty-seven patients undergoing chemotherapy for osteosarcoma underwent evaluation with magnetic resonance (MR) imaging to identify changes related to a good or poor response. Spin-echo MR images obtained after preoperative chemotherapy were compared with images obtained before treatment. Histopathologic examination of each resected specimen was used to quantify the response. An increase in tumor volume and increased or unchanged edema were predictive of a poor histopathologic response (predictive values, 85%-92%). Decreased or unchanged tumor volume and a decrease in edema were poor predictors of a good response (predictive values, 56%-62%). Improved tumor demarcation, an increase in the size of areas of low signal intensity, and a decrease in joint effusion occurred independently of histopathologic response in almost half of the patients. With a subjective interpretation of MR images, poor respondents can be identified if an increase in tumor volume or no decrease in the amount of edema is seen. Subjective criteria do not contribute to the identification of good respondents.
From January 1974 to September 1991, 245 consecutive patients with severe aplastic anemia underwent bone marrow transplantation at the Hôpital Saint-Louis, Paris, France. Five cases of solid tumor were observed overall, a number that leads to an 8-year cumulative incidence rate of 7.7% (95% CL: 0.9%, 14.5%). Relative to the general population, the risk was equal to 22 (95% CL: 7, 51; p < 0.001). The present report focuses on the unusual clinical course of patients developing malignant tumors after bone marrow transplantation for severe aplastic anemia. It also aims at reporting the difficulty encountered in comparing data from different sources.
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In the absence of systematic immunohistochemistry investigations, only 25 cases (out of 69) clearly diagnosed as neurosarcoma due to the association with Von Recklinghausen disease (ie, neurofibromatosis type 1) and treated at the Institut Gustave Roussy were included in the present study. Neurosarcoma consists of a neurocristopathy whose cells migrate to several parts of the body in order to constitute neuroglia, Schwann cells, pigmented and endocrinal tissues. From 1967 to 1990, 25 cases of such neurosarcomas associated with a neurofibromatosis type 1 were seen at our institute. Three different histological terms exist for this tumour: malignant schwannoma, neurosarcoma, and more recently, malignant peripheral nerve sheath tumours (MPNST). The median age (23 years) of the patients with neurofibromatosis type 1 is lower than that of patient with isolated neurosarcoma. Their sex ratio is 2/1. Primary tumour surgical exeresis was performed in all cases, with poor results in 7. Post-operative radiation therapy was not systematically used in this series. It was administered only in cases with incomplete surgical exeresis or when a local recurrence occurred. Adjuvant CYVADIC (doxorubicin, procarbazine, cyclophosphamide, vincristine) chemotherapy was administered in 5 cases, of in cases of relapse (8). All cases but 2 (the most recent ones) relapsed within 1 to 226 months (median 7 months). In addition, 13 patients developed metastases. Overall, the 2-year and 4-year survival rates were 41% and 18%, respectively. Our observations confirm the very poor prognosis for the association of neurofibromatosis type 1 and neurosarcoma. This finding should lead to systematically associate radical surgical exeresis, post-operative irradiation and adjuvant chemotherapy in the treatment of these patients.
Studies of the effectiveness of hematopoietic cell growth factors for improving recovery from chemotherapy-induced neutropenia use the duration of neutropenia as the main end-point. To determine the effect of time of analysis and transportation on the reliability of blood counts, 40 blood samples from patients with neutropenia (neutrophils between 0.5 and 1.0 x 10(9)/L) were studied immediately after sampling then after 8, 24 and 48 hours (time factor). Some of the specimens were taken from patients hospitalized in an institution located at some distance from the laboratory and were used to evaluate the effect of specimen transportation on results. Of the three methods tested (blood smear, coulter-counter, and Malassez counting chamber), the blood smear proved the most reliable. Neutrophil counts did not change over time, although morphologic changes with a potential for causing problems in neutrophil recognition were seen. No definite conclusions can be drawn from the transportation study although variations were seen in transported versus non transported specimens. These data show that blood specimens can be analyzed without changing normal working hours. However, no more than 8 hours should be allowed to elapse between sampling and processing.
From May 1980 to December 1989, 107 consecutive patients with non-constitutional severe aplastic anemia underwent bone marrow transplantation at our institution using cyclophosphamide and thoraco-abdominal irradiation as conditioning regimen. During the same period, 40 patients with Fanconi anemia were also grafted after a similar conditioning, giving a total series of 147 patients. With a mean follow-up of 64 months, four male patients developed a solid malignant tumor, a number that leads to an 8-year cumulative incidence rate of 22% (eg, relative risk to general population = 41, P less than .001). These results should be considered as a warning to clinicians who follow these successfully grafted long-term patients.
OBJECTIVE: To assess the value of an elevated (greater than 30 mm/h) Westergren erythrocyte sedimentation rate (ESR) for predicting early relapse and survival after therapy in patients with clinical stage I or II Hodgkin disease. INTERVENTIONS: We studied 772 patients with early-stage Hodgkin disease who had participated in two separate multicenter clinical trials. Both trials used modern field radiotherapy and, in some patients, multi-agent chemotherapy. MAIN RESULTS: The ESR patterns were based on pretherapy and post-therapy assessments: pattern 1, always normal (n = 261); pattern 2, elevated before therapy but normal immediately after therapy (n = 121); pattern 3, elevated before therapy but normal within 3 months after therapy (n = 89); pattern 4, always elevated (n = 48); pattern 5, normal before therapy but oscillating between normal and elevated after therapy (n = 150); pattern 6, elevated before therapy but oscillating between normal and elevated after therapy (n = 130). By multivariate analysis, independent of whether or not patients received chemotherapy in the initial therapy protocol, ESR patterns 4, 5, and 6 were shown to be the best predictors for early relapse and survival when patients were stratified according to the type of chemotherapy received and the number of involved nodal areas. Patients with ESR pattern 4 had a relative risk for death seven times that of patients with patterns 1, 2, or 3. Early relapse was the second most important factor predicting death, irrespective of ESR; patients with early relapse and ESR patterns 1, 2, or 3 had a relative risk for death of 4.5, and those with early relapse and ESR patterns 4, 5, or 6 had a relative risk for death of 15. Whether or not chemotherapy was given initially did not change the relative risk, which shows that ESR, not initial therapy, was the predictor for early relapse and death due to Hodgkin disease. CONCLUSION: An unexplained elevated ESR after therapy, especially after modern radiotherapy, independent of other factors, strongly suggest the presence of aggressive and resistant Hodgkin disease. An elevated ESR is predictive of early relapse and poor prognosis; its presence justifies early aggressive therapy.
An analysis was performed of all 57 early relapses (ER) (within 18 months of therapy initiation) seen in a group of 301 patients treated on three successive European Organization for Research and Treatment of Cancer (EORTC) protocols from 1964 to 1981; to determine whether a posttherapy elevated erythrocyte sedimentation rate (ESR) (greater than or equal to 30 mm) could predict the type of relapse and the effect upon the relapse of different therapies received. Overall most ER occurred in extranodal (EN) (42%) or irradiated transdiaphragmatic nodal (TDN) (40%) sites. Compared to patients with normal posttherapy ESR (n = 12), patients with elevated posttherapy ESR (n = 45) had the same proportions of outfield and late relapses; more frequent multiple sites of ER (38% vs. 25%), increased proportions of early EN relapses (16% vs. 3%), TDN relapses (17% vs. 2%), and other ER (6% vs. 1%). ER were most frequently observed between 1964 and 1971, and "modern" radiotherapy (Rt) decreased ER overall from 27% to 13% and for elevated posttherapy ESR patients from 54% to 25%. When chemotherapy (Ct) was used as either adjuvant or initial therapy, ER were greatly reduced vs. Rt alone [overall (6% vs. 28%) and for patients with elevated posttherapy ESR (10% vs. 39%)]. Stepwise logistic regression showed Ct to be the most important factor "protecting" from EN relapse, but elevated posttherapy ESR was still significant. For early TDN relapse, elevated posttherapy ESR had the highest predictive value for relapse, greater than the types of radiation fields used and chemotherapy. An unexplained elevated posttherapy ESR, regardless of previous therapy, predicts for ER from aggressive HD, frequently in EN and irradiated areas, and warrants further early therapy.
The EORTC Lymphoma Cooperative Group and the Pierre and Marie Curie Group conducted a multicentre randomised trial on clinical stages IIIB-IV Hodgkin's disease from 1981-1986. Two hundred seven patients were registered and 192 randomised. Actuarial survival at five years for the whole group was 68%. Induction chemotherapy with eight cycles of MOPP resulted in more patients with progressive disease and fewer partial responders than a combination of MOPP and ABVD, for an equal complete remission rate. Half of the partial responders went into complete remission after radiotherapy. At five years there was no significant survival difference between the arms. Progression was recorded in 39 patients of whom only 4 survived. Relapses were most frequent in previously involved unirradiated areas. For 46 relapsed patients, including 21 early relapses within 18 months of start of treatment, the four-year survival rate was 53%. When complete remission was reached, whether early or late with combination chemotherapy or after additional radiotherapy, prognosis was independent of the way in which it was achieved. All efforts should be taken to reach a complete remission for initially progressing patients and for partial responders.
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.
From 1971 to 1984, 499 patients with all stages of Hodgkin's 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 Hodgkin's 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.
Whether or not pregnancy adversely affects the natural course of underlying primary renal disease, and whether fetal outcome is influenced by the type of renal disease per se are controversial issues. We retrospectively analyzed the fetal and maternal outcome in 148 women with various, biopsy-proven histological types of primary chronic glomerulonephritis (GN), including IgA GN (52 patients), membranous GN ([MGN] 20 patients), membranoproliferative type 1 GN ([MPGN] 58 patients), focal and segmental glomerulosclerosis ([FSGS] 13 patients), and minimal change nephrotic syndrome ([MCNS] 22 patients), who were pregnant (with a total of 290 pregnancies) after the clinical onset of GN, and in 104 women with reflux nephropathy (with a total of 254 pregnancies). Fetal outcome was poor in the presence of uncontrolled hypertension, nephrotic range proteinuria, and/or impaired renal function at conception or early in gestation, whatever the type of renal disease. An accelerated, more rapid than expected, worsening of maternal renal function was observed in five GN patients of whom four (two IgA, two MPGN) had serum creatinine (Scr) levels greater than 160 mumol/L (1.8 mg/dL) early in gestation, and in five patients with reflux nephropathy whose Scr at conception ranged from 180 to 490 mumol/L (2.0 to 5.5 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)