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Purpose: While patients with early-stage Hodgkin lymphoma (HL) have an excellent outcome with combined treatment, the radiation therapy (RT) dose and treatment with chemotherapy alone remain questionable. This noninferiority trial evaluates the feasibility of reducing the dose or omitting RT after chemotherapy., Methods and Materials: Patients with untreated supradiaphragmatic HL without risk factors (age ≥ 50 years, 4 to 5 nodal areas involved, mediastinum-thoracic ratio ≥ 0.35, and erythrocyte sedimentation rate ≥ 50 mm in first hour without B symptoms or erythrocyte sedimentation rate ≥ 30 mm in first hour with B symptoms) were eligible for the trial. Patients in complete remission after chemotherapy were randomized to no RT, low-dose RT (20 Gy in 10 fractions), or standard-dose involved-field RT (36 Gy in 18 fractions). The limit of noninferiority was 10% for the difference between 5-year relapse-free survival (RFS) estimates. From September 1998 to May 2004, 783 patients received 6 cycles of epirubicin, bleomycin, vinblastine, and prednisone; 592 achieved complete remission or unconfirmed complete remission, of whom 578 were randomized to receive 36 Gy (n=239), 20 Gy of involved-field RT (n=209), or no RT (n=130)., Results: Randomization to the no-RT arm was prematurely stopped (≥20% rate of inacceptable events: toxicity, treatment modification, early relapse, or death). Results in the 20-Gy arm (5-year RFS, 84.2%) were not inferior to those in the 36-Gy arm (5-year RFS, 88.6%) (difference, 4.4%; 90% confidence interval [CI] -1.2% to 9.9%). A difference of 16.5% (90% CI 8.0%-25.0%) in 5-year RFS estimates was observed between the no-RT arm (69.8%) and the 36-Gy arm (86.3%); the hazard ratio was 2.55 (95% CI 1.44-4.53; P<.001). The 5-year overall survival estimates ranged from 97% to 99%., Conclusions: In adult patients with early-stage HL without risk factors in complete remission after epirubicin, bleomycin, vinblastine, and prednisone chemotherapy, the RT dose may be limited to 20 Gy without compromising disease control. Omitting RT in these patients may jeopardize the treatment outcome., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: For early-stage Hodgkin lymphoma (HL), optimal chemotherapy regimen and the number of cycles to be delivered remain to settle down. The H9-U trial compared three modalities of chemotherapy followed by involved-field radiotherapy (IFRT) in patients with stage I-II HL and risk factors (NCT00005584)., Patients and Methods: Patients aged 15-70 years with untreated supradiaphragmatic HL with at least one risk factor (age ≥ 50, involvement of 4-5 nodal areas, mediastinum/thoracic ratio ≥ 0.35, erythrocyte sedimentation rate (ESR) ≥ 50 without B-symptoms or ESR ≥ 30 and B-symptoms) were eligible for the randomised, open label, multicentre, non-inferiority H9-U trial. The limit of non-inferiority was set at 10% for the difference between 5-year event-free survival (EFS) estimates. From October 1998 to September 2002, 808 patients were randomised to receive either the control arm 6-ABVD-IFRT (n = 276), or one of the two experimental arms: 4-ABVD-IFRT (n = 277) or 4-BEACOPP baseline -IFRT (n = 255)., Results: Results in the 4-ABVD-IFRT (5-year EFS, 85.9%) and the 4-BEACOPP baseline -IFRT (5-year EFS, 88.8%) were not inferior to 6-ABVD-IFRT (5-year EFS, 89.9%): difference of 4.0% (90%CI, -0.7%-8.8%) and of 1.1% (90%CI,-3.5%-5.6%) respectively. The 5-year overall survival estimates were 94%, 93%, and 93%, respectively. Patients treated with combined modality treatment chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vincristine (Oncovin), cyclophosphamide, procarbazine, etoposide and prednisone (BEACOPP) baseline more often developed serious adverse events requiring supportive measures and hospitalisation compared with patients receiving the chemotherapeutic regimen comprising doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD)., Conclusions: The trial demonstrates that 4-ABVD followed by IFRT yields high disease control in patients with early-stage HL and risk factors responding to chemotherapy. Although non-inferior in terms of efficacy, four cycles of BEACOPP baseline were more toxic than four or six cycles of ABVD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Study Question: How does the successful cryopreservation of semen affect the odds of post-treatment fatherhood among Hodgkin lymphoma (HL) survivors?, Summary Answer: Among 334 survivors who wanted to have children, the availability of cryopreserved semen doubled the odds of post-treatment fatherhood., What Is Known Already: Cryopreservation of semen is the easiest, safest and most accessible way to safeguard fertility in male patients facing cancer treatment. Little is known about what proportion of patients achieve successful semen cryopreservation. To our knowledge, neither the factors which influence the occurrence of semen cryopreservation nor the rates of fatherhood after semen has been cryopreserved have been analysed before., Study Design, Size, Duration: This is a cohort study with nested case-control analyses of consecutive Hodgkin survivors treated between 1974 and 2004 in multi-centre randomized controlled trials. A written questionnaire was developed and sent to 1849 male survivors., Participants/materials, Setting, Methods: Nine hundred and two survivors provided analysable answers. The median age at treatment was 31 years. The median follow-up after cryopreservation was 13 years (range 5-36)., Main Results and the Role of Chance: Three hundred and sixty-three out of 902 men (40%) cryopreserved semen before the start of potentially gonadotoxic treatment. The likelihood of semen cryopreservation was influenced by age, treatment period, disease stage, treatment modality and education level. Seventy eight of 363 men (21%) used their cryopreserved semen. Men treated between 1994 and 2004 had significantly lower odds of cryopreserved semen use compared with those treated earlier, whereas alkylating or second-line (chemo)therapy significantly increased the odds of use; no other influencing factors were identified. We found an adjusted odds ratio of 2.03 (95% confidence interval 1.11-3.73, P = 0.02) for post-treatment fatherhood if semen cryopreservation was performed. Forty-eight out of 258 men (19%) who had children after HL treatment became a father using cryopreserved semen., Limitations, Reasons for Caution: Data came from questionnaires and so this study potentially suffers from response bias. We could not perform an analysis with correction for duration of follow-up or provide an actuarial use rate due to lack of dates of semen utilization. We do not have detailed information on either the techniques used in cryopreserved semen utilization or the number of cycles needed., Study Funding/competing Interests: Lance Armstrong Foundation, Dutch Cancer Foundation, René Vogels Stichting, no competing interests.

Purpose: In this large cohort of Hodgkin's lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment., Patients and Methods: The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe d'Étude des Lymphomes de l'Adulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis., Results: Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine; epirubicin, bleomycin, vinblastine, and prednisone). Dose relationship between alkylating chemotherapy and POF occurrence was linear. POF risk increased by 23% per year of age at treatment. In women treated without alkylating chemotherapy at age younger than 32 years and age 32 years or older, cumulative POF risks were 3% (95% CI, 1% to 16%) and 9% (95% CI, 4% to 18%), respectively. If menstruation returned after treatment, cumulative POF risk was independent of age at treatment. Among women who ultimately developed POF, 22% had one or more children after treatment, compared with 41% of women without POF., Conclusion: Nonalkylating chemotherapy carries little to no excess risk of POF. Dose-response relationships for alkylating chemotherapy and age at treatment are both linear. Timely family planning is important for women at risk of POF.

Background: Although widely recommended, cryopreservation of sperm is sometimes not performed for patients with Hodgkin's lymphoma because of presumed poor sperm quality related to the disease. We investigated sperm quality and factors determining it in untreated patients with early stage Hodgkin's lymphoma., Design and Methods: Of 2362 males who participated in EORTC H6-H9 trials, 474 (20%) had data available. Sperm quality was defined according to World Health Organization guidelines. Determining factors were studied by logistic regression analysis., Results: The median sperm concentration was 40x10(6)/mL (range, 0-345x10(6)/mL) and the median motility 50% (range, 0-90%). Sperm quality was good (concentration >or=20x10(6)/mL and motility >or=50%), intermediate (concentration >or=5x10(6)/mL) and poor (concentration <5x10(6)/mL but >0) in 41%, 49% and 7% of patients, respectively. Three percent of the patients were azoospermic. No relation was found between sperm quality and age or clinical stage of the Hodgkin's lymphoma, but B-symptoms and elevated erythrocyte sedimentation rate predicted poor sperm quality. The odds ratios for the association of poor sperm quality with the variables examined were: presence of B-symptoms, 2.77 (95% CI, 1.50-5.12; p=0.001); erythrocyte sedimentation rate of 50 mm/h or greater, 2.35 (95% CI, 1.24-4.43; p=0.009); fever, 3.22 (95% CI, 1.41-7.33; p=0.005), and night sweats, 3.78 (95% CI, 1.97-7.26; p<0.001). There was no relation between sperm quality and pre-treatment follicle stimulating hormone level., Conclusions: In this large study of males with Hodgkin's lymphoma, 90% had good or intermediate sperm quality. Three percent were azoospermic. There was an association between sperm quality and the presence or absence of B-symptoms, in particular fever and night sweats. With modern fertilization techniques, in most patients with early-stage Hodgkin's lymphoma sperm quality before treatment is good enough for future fatherhood.

Background: Little is known about the longitudinal course of health-related quality of life (HRQoL) in patients with Hodgkin's lymphoma during their post-treatment follow-up and re-adaptation to normal life. We report on the HRQoL of patients treated in the randomised H8 trial of the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group and the Groupe d'Etudes des Lymphomes de l'Adulte (GELA). We aimed to assess HRQoL and fatigue following treatment, to analyse relations with treatment, and to identify factors that predict persistent fatigue., Methods: Patients received HRQoL questionnaires at the end of primary therapy and during follow-up. The EORTC QLQ-C30 was used to assess HRQoL, and the Multidimensional Fatigue Inventory (MFI-20) was used to assess fatigue. Changes of mean HRQoL scores over time were analysed with mixed models. Multiple polytomic nominal logistic regression was done to identify independent baseline predictors of fatigue within MFI-20 dimensions. Analyses were done on an intention-to-treat basis. This study is registered with www.ClinicalTrials.gov, number NCT00379041., Findings: 2666 assessments from 935 patients were analysed. Mean follow-up was 90 months (range 52-118). Age affected all functioning and symptom scores except emotional functioning, with younger age associated with higher functioning and lower severity of symptoms; improvement with time showed similar patterns between age groups. Women reported lower HRQoL and higher symptom scores than did men. Overall, 3.2% (14/439 for role functioning) to 9.7% (43/442 for social functioning) and 5.8% (29/498 for reduced motivation) to 9.9% (49/498 for general fatigue) of patients reported impairments of 10 points or more (on a 0-100 scale) in QLQ-C30 and MFI-20 scores, respectively, independent of age and sex. Emotional domains were more affected than physical ones. There was no relation between HRQoL outcome and type of treatment. Fatigue (MFI-20 scores) at the end of treatment was the only predictive variable for persistent fatigue, with odds ratios varying from 2.58 (95% CI 1.00-6.67) to 41.51 (12.02-143.33; p

Background: Treatment of early-stage Hodgkin's disease is usually tailored in line with prognostic factors that allow for reductions in the amount of chemotherapy and extent of radiotherapy required for a possible cure., Methods: From 1993 to 1999, we identified 1538 patients (age, 15 to 70 years) who had untreated stage I or II supradiaphragmatic Hodgkin's disease with favorable prognostic features (the H8-F trial) or unfavorable features (the H8-U trial). In the H8-F trial, we compared three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) combined with doxorubicin, bleomycin, and vinblastine (ABV) plus involved-field radiotherapy with subtotal nodal radiotherapy alone (reference group). In the H8-U trial, we compared three regimens: six cycles of MOPP-ABV plus involved-field radiotherapy (reference group), four cycles of MOPP-ABV plus involved-field radiotherapy, and four cycles of MOPP-ABV plus subtotal nodal radiotherapy., Results: The median follow-up was 92 months. In the H8-F trial, the estimated 5-year event-free survival rate was significantly higher after three cycles of MOPP-ABV plus involved-field radiotherapy than after subtotal nodal radiotherapy alone (98% vs. 74%, P<0.001). The 10-year overall survival estimates were 97% and 92%, respectively (P=0.001). In the H8-U trial, the estimated 5-year event-free survival rates were similar in the three treatment groups: 84% after six cycles of MOPP-ABV plus involved-field radiotherapy, 88% after four cycles of MOPP-ABV plus involved-field radiotherapy, and 87% after four cycles of MOPP-ABV plus subtotal nodal radiotherapy. The 10-year overall survival estimates were 88%, 85%, and 84%, respectively., Conclusions: Chemotherapy plus involved-field radiotherapy should be the standard treatment for Hodgkin's disease with favorable prognostic features. In patients with unfavorable features, four courses of chemotherapy plus involved-field radiotherapy should be the standard treatment. (ClinicalTrials.gov number, NCT00379041 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Purpose: To analyze fertility in male patients treated with various combinations of radiotherapy and chemotherapy, with or without alkylating agents, or with radiotherapy alone for Hodgkin's lymphoma., Patients and Methods: Follicle-stimulating hormone (FSH) levels were measured in patients with early-stage upper-diaphragmatic disease enrolled in four European Organisation for Research and Treatment of Cancer (EORTC) trials (H6-H9). Median follow-up after therapy was 32 months. Patients with FSH measurement at least 12 months after end of treatment (n = 355) were selected to assess post-treatment fertility. Patients with FSH measurement 0 to 9 months after therapy (n = 349) were selected to analyze fertility recovery; of these, patients with elevated FSH (> 10 U/L; n = 101) were followed until recovery. Factors predictive for therapy-related infertility were assessed by logistic regression., Results: The proportion of elevated FSH was 3% and 8% in patients treated with radiotherapy only or with nonalkylating chemotherapy (doxorubicin, bleomycin, vinblastine, dacarbazine [ABVD], epirubicin, bleomycin, vinblastine, prednisone [EBVP]); it was 60% (P < .001) after chemotherapy containing alkylating agents (mechlorethamine, vincristine, procarbazine, prednisone [MOPP], MOPP/doxorubicin, bleomycin, vinblastine [ABV], bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone [BEACOPP]). After a median time of 19 months, recovery of fertility occurred in 82% of patients treated without alkylating chemotherapy. This proportion was 30%, statistically (P < .001) lower in those treated with alkylating chemotherapy, and median time to recovery was 27 months. The post-treatment proportion of elevated FSH increased significantly (P < .001) with the dose of alkylating chemotherapy administered, and recovery was less frequent and slower after higher doses. Age more than 50 years and stage II disease also contributed to poor outcome., Conclusion: Fertility can be secured after nonalkylating chemotherapy for Hodgkin's lymphoma. In contrast, alkylating chemotherapy has a dismal effect, even after a limited number of cycles.

Background: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial., Patients and Methods: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method., Results: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25)., Conclusions: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Purpose: In early-stage Hodgkin's lymphoma (HL), subtotal nodal irradiation (STNI) and combined chemotherapy/radiotherapy produce high disease control rates but also considerable late toxicity. The aim of this study was to reduce this toxicity using a combination of low-intensity chemotherapy and involved-field radiotherapy (IF-RT) without jeopardizing disease control., Patients and Methods: Patients with stage I or II HL were stratified into two groups, favorable and unfavorable, based on the following four prognostic factors: age, symptoms, number of involved areas, and mediastinal-thoracic ratio. The experimental therapy consisted of six cycles of epirubicin, bleomycin, vinblastine, and prednisone (EBVP) followed by IF-RT. It was randomly compared, in favorable patients, to STNI and, in unfavorable patients, to six cycles of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV hybrid) and IF-RT., Results: Median follow-up time of the 722 patients included was 9 years. In 333 favorable patients, the 10-year event-free survival rates (EFS) were 88% in the EBVP arm and 78% in the STNI arm (P = .0113), with similar 10-year overall survival (OS) rates (92% v 92%, respectively; P = .79). In 389 unfavorable patients, the 10-year EFS rate was 88% in the MOPP/ABV arm compared with 68% in the EBVP arm (P < .001), leading to 10-year OS rates of 87% and 79%, respectively (P = .0175)., Conclusion: A treatment strategy for early-stage HL based on prognostic factors leads to high OS rates in both favorable and unfavorable patients. In favorable patients, the combination of EBVP and IF-RT can replace STNI as standard treatment. In unfavorable patients, EBVP is significantly less efficient than MOPP/ABV.

Purpose: To evaluate the impact of the quality of involved-field radiotherapy (IFRT) on clinical outcome in patients with advanced Hodgkin's lymphoma (HL) in complete remission (CR) after six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisone-doxorubicin, bleomycin, and vinblastine (MOPP-ABV) chemotherapy., Methods and Materials: A retrospective review of clinical and radiologic data, radiation charts, simulator films, and megavoltage (MV) photographs was performed. IFRT consisted of 24 Gy to all initially involved nodal areas and 16-24 Gy to all initially involved extranodal sites. Major violations were defined as no or only partial irradiation of an originally involved area, or a total dose <90% of the prescribed dose., Results: Of the 739 patients who were enrolled in the trial between 1989 and 2000, 57% achieved a CR; 152 of 172 patients randomized to IFRT actually received radiotherapy; and in 135 patients, quality control was performed. The overall major violation rate was 47%, predominantly concerning target volumes. The total dose was correct in 81% of the patients. After a median follow-up of 6.5 years, there was no difference in cumulative failure rate between patients with or without major violations. There was no relationship between incidence or site of relapse and major protocol violations., Conclusion: In advanced-stage HL patients in complete remission after six to eight cycles of MOPP-ABV, the outcome was not influenced by violation of the radiotherapy protocol.

Background: The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin's lymphoma is controversial., Methods: We randomly assigned patients with previously untreated stage III or IV Hodgkin's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP-ABV) to receive either no further treatment or involved-field radiotherapy. Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites. Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites., Results: Of 739 patients, 421 had a complete remission; 161 of these patients were assigned to no further treatment, and 172 to involved-field radiotherapy. The median follow-up was 79 months. The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that received involved-field radiotherapy (P=0.35). The five-year overall survival rates were 91 and 85 percent, respectively (P=0.07). Among the 250 patients in partial remission after chemotherapy, the five-year event-free and overall survival rates were 79 and 87 percent, respectively., Conclusions: Involved-field radiotherapy did not improve the outcome in patients with advanced-stage Hodgkin's lymphoma who had a complete remission after MOPP-ABV chemotherapy. Radiotherapy may benefit patients with a partial response after chemotherapy., (Copyright 2003 Massachusetts Medical Society)

Important progress have been recently achieved in the management of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Prognostic factors are now better defined in HD thanks to new biologic and radiologic information which complete old and relevant clinical factors. These parameters are expected to improve decision making in patient's management. However, treatment strategy is under new discussion and controversies about the role of radiotherapy and its doses. There are now enough arguments to consider radiotherapy unnecessary in advanced stages when a complete remission is achieved by chemotherapy. There is also important concern about late effects of treatment and not only secondary cancers. Non-Hodgkin's lymphomas are heterogeneous and different entities are now better defined and described, thanks to a common and similar language for immunological clinical data and treatment outcome. New strategies are under investigation using monoclonal antibodies with or without radioisotopes, in association with chemotherapy or radiotherapy. Undoubtedly, these new approaches are going to improve the overall prognosis of NHL.

In spite of the fact that Hodgkin's disease (HD) remains still an enigma its management and treatment yield a cure rate of about 80% of all patients. However, this management has two limits: on one side favourable cases which should not be overtreated because of unacceptable side-effects, and on the other side very unfavourable cases which should be treated differently because of a very high rate of failure and/or relapse. Then it becomes necessary to precise as thoroughly as possible these two limits in order to choose the adequate treatment for the patient. Prognostic factors based on patient and disease characteristics allow a relatively exact classification of favourable and unfavourable cases. This distinction in two prognostic groups has therapeutic implications in terms of chemotherapy (regimen, duration) and radiotherapy (extension, doses). Other specific situations have to be considered, e.g. pediatric cases, pregnancy, old age and HIV-infected patients who need an adapted management according to very different situations.

Background: The prophylaxis of the late effects of chemotherapy and radiotherapy has become one of the major concerns in the management of Hodgkin's disease (HD). Unlike other complications, male sterility could be managed by prior semen preservation (SP)., Patients and Methods: To evaluate the semen quality of patients with HD and the outcome of insemination, we reviewed spermograms of patients who underwent SP before any treatment. The following criteria were necessary: 1) age > 16 and < 50; 2) HD of any stage; 3) informed about male sterility after HD treatment; 4) fully consenting., Results: Such a proposal was made to 316 men, and 94 fulfilled the criteria. All patients underwent an initial chemotherapy. Mean age of the cohort was 27.5 years (range 16-48 years). Pretherapeutic staging of HD revealed 38 stage I (40%), 38 II (38%), 14 III (15%) and 4 IV (4%). Semen analysis before cryoconservation showed an overall 53% of normal or subnormal cases (50 cases). The analysis of semen quality and spermatozoid amount according to various parameters failed to find a correlation with stage, B symptoms, age, or biologic data (LDH, WBC, platelets, ESR). The use of cryopreserved semen was requested by 13 patients; 88 inseminations were performed leading to 9 pregnancies and 2 births., Conclusions: The low rate of success with cryopreserved semen in these cases suggests the need for a more careful design of non-toxic chemotherapy regimens in combined modality treatment.

Previous reports from available trials have dealt with negative long-term sequelae in Hodgkin's disease (HD) survivors. There is, however, a lack of longitudinal data showing the correlation between outcome and various treatment-related variables and the process of re-adaptation into normal life after the end of treatment. In order to investigate the quality of life (QoL) of patients with HD in different dimensions during active treatment and follow-up and to identify longitudinal patterns of QoL dimensions during re-adaptation to normal life within the EORTC Lymphoma Cooperative Group and Groupe D'Etude des Lymphomes de L'Adulte (EORTC/GELA) and the German Hodgkin Study Group (GHSG), QoL assessment strategies were put into use over the last three to five years. Furthermore, the efforts aimed at obtaining cross-cultural comparisons between the participating countries and study groups (EORTC/GELA and GHSG). Within the randomised EORTC/GELA Trial 'H8' for clinical stage I-II HD which started in September 1993, patients receive a QoL questionnaire for completion at each follow-up visit during the first 10 years after the end of active therapy. The corresponding 'HD8' study of the GHSG employs the assessment of QoL during and after active treatment periods. Within both studies, the EORTC QLQ C30 is used for QoL assessment incorporated in the QLQ-S (quality of life questionnaire for survivors), which additionally addresses the aspects of fatigue/malaise, sexuality, specific side effects, and retrospective evaluation of treatment. In total the QLQ-S includes 45 questions on 14 functional, symptom, and fatigue scales, 15 additional single items, and 3 open questions. In addition to the longitudinal QoL assessment, the GHSG carried out cross-sectional QoL trials with all cured surviving patients from the past HD1-6 studies and a matched normal control sample employing the QLQ-S and the life situation questionnaire (LSQ), an instrument covering objective data from 45 domains of life. To date, within the trials H8 and HD8 over 3000 QoL questionnaires from more than 800 patients from ten countries are available for analysis. Replication of the psychometric properties of the scales revealed satisfactory results using factor analyses and reliability testing across languages for the QLQ-S. A feasibility analysis showed generally a good acceptance of the questionnaire by the patients and physicians. QoL assessment within international multicentre trials in HD proved feasible within the two differently organised study groups of EORTC/GELA and GHSG. The use of subjective QoL data (QLQ-S) together with objective data (LSQ) in a combined cross-sectional and longitudinal trial system will give the most comprehensive insight into the problems of the re-integration process into normal life after cure. This information will provide the basis for the development of remedies/help measures and possible modifications of treatment strategies. The current approach will be further developed in close collaboration between both trial groups, and next steps will include translation of the LSQ into other languages and adaptation to various cultural circumstances.

The pathological material of 35 patients with Hodgkin's disease lymphocyte-depletion type (type 4) is reviewed with an immunohistochemistry study on paraffin-embedded sections. The new pathologic data are compared with clinical features. These 35 patients are 4.7% of 742 previously untreated patients managed in this institution from 1960 to 1991. The diagnosis of 31 of the 35 patients was rectified, 17 to non-Hodgkin's lymphoma (12 unclassifiable and five anaplastic Ki-1 positive) and 14 to another type of Hodgkin's disease (six nodular sclerosis and eight mixed cellularity). In four cases, the pathologic material was neither sufficient nor satisfactory to allow a clear-cut distinction between Hodgkin's disease and non-Hodgkin's lymphoma. The analysis of clinical data before and after pathological revision did not show any difference in clinical features, either between Hodgkin's disease "type 4" and other types (1, 2 or 3) or between cases with Hodgkin's disease and those with non-Hodgkin's lymphoma. There is, however, a significant male predominance for Hodgkin's disease versus non-Hodgkin's lymphoma (P = 0.029, exact Fisher test), and B symptoms in non-Hodgkin's lymphomas (P = 0.056), whereas B symptoms are commonly seen in advanced stages of Hodgkin's disease. It is emphasized that all Hodgkin's disease of lymphocyte-depletion type should be reviewed and discussed before any treatment, and this diagnosis actually means non-Hodgkin's lymphoma or other types of Hodgkin's disease.

In this phase III trial, 770 patients with clinical stage I-II Hodgkin's disease (HD) have been enrolled since November 1988. Preliminary results are given for the 605 (79%) patients who have completed their initial therapy. Patients were grouped according to 6 pretreatment prognostic characteristics. In the very favourable (VF) group, treatment consisted of mantle field alone. In the favourable (F) group, patients were randomized to either subtotal nodal irradiation (STNI), or 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone) followed by involved-field irradiation (IF-RT). Unfavourable (U) patients were randomized to either 6 cycles of EBVP plus IF-RT, or to 6 cycles of MOPP/ABV hybrid plus IF-RT. Of the 35 VF patients, none have progressed during radiotherapy. Four patients relapsed and were salvaged. Three-year failure-free survival (FFS) was 82%; overall survival (OS) was 100%. Of the 254 F patients, 130 were treated with STNI and 124 with EBVP plus IF-RT. At 3 years, FFS rates were 81% (1 progression, 14 relapses) and 79% (5 progressions, 8 relapses), respectively. Corresponding OS rates were 99% and 100%. Of the 316 U patients, 160 received EBVP and 156 MOPP/ABV. At 3 years, FFS rates were 72% (18 progressions, 20 relapses) and 88% (7 progressions, 6 relapses), respectively (p < 0.001). Although OS rates were identical (92%), the entry in the U-EBVP arm was stopped in November 1992. We conclude that a treatment strategy based on prognostic factors allows the use of less aggressive treatment in favourable patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors report 11 cases of Hodgkin's disease in which the first sign was due to bone involvement. Such observations are rare and raise diagnosis delays (Means: 5, 6 months in this series). Modern medical imaging techniques (scintigraphy, CT scan, magnetic resonance imaging) are very useful to an earlier diagnosis which will be better confirmed by lymph node biopsy given the poor information yielded by osseous cytology and/or histology. The elective localisation in bones belonging to the axial skeleton seems to support the hypothesis of a contiguous osseous involvement from lymphoïd organs in contact with bones. Evolution with chemotherapy and radiotherapy is very similar to that observed in patients without bone involvement.

A novel combination of epirubicin, bleomycin, vinblastine and prednisone (EBVP II) was scheduled to reduce the toxicity of chemotherapy and to improve its application in treatment of Hodgkin's disease. This combination followed a previous regimen given every 15 days (EBVP I) by the same cooperative group. EPVP II is given every 21 days with increased dosage and increased intensity of epirubicin. This regimen was given to 100 consecutive patients with favourable or unfavourable limited-stage disease (clinical stages I-IIIA) excluding very favourable stages I and II and stages IIIB and IV. Such patients first received three injections of EBVP II and were then radically irradiated; those with unfavourable prognosis factors received three subsequent injections of EBVP II. The present analysis reports the early results of such treatment and considers particularly toxicity and the obtention of complete remission, which is pre-eminent for a cure. EBVP II was given in full dosage in 99% of the primary set of three injections. The main toxicity was alopecia and to a lesser degree nausea and vomiting and veinitis. Complete remission was obtained in 76 patients before radiotherapy and in 20 others after radiotherapy. With a median follow-up of 30 months 1 patient died from Hodgkin's disease, 9 are alive after relapse and 90 with no evidence of disease. This treatment appears to be as efficient as previous chemotherapy, well tolerated and particularly easy to give. It deserves further comparison with other proved regimens taking into consideration the survival and quality of life of patients.

The purpose of this report is to assess whether phenotyping by three monoclonal antibodies routinely used in paraffin sections (Ber-H2-Leu-M1-EMA) and shown to be the most useful for diagnosis may be a predictive factor for recurrences. Among 563 patients diagnosed as having Hodgkin's disease (24% of whom had recurrence), we selected 153 patients with and without recurrence, with matching clinical stage. For all of these cases, histologic material was tested by immunostainings with satisfactory control samples. No phenotype was specific for Hodgkin's disease, although the phenotype Ber-H2-Leu-M1-EMA was predominant. No phenotype was found to be a predictive factor for recurrences, and none was unchanged during the clinical course, except when recurrence occurred as non-Hodgkin's lymphoma.

In order to reduce, if not completely suppress, late complications of combined chemotherapy and radiotherapy in Hodgkin's disease (HD), MOPP regimen (mechlorethamine, vincristine, procarbazine and prednisone) was replaced by ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Ninety-four patients with HD clinical stages I to IIIA with no staging laparotomy were treated by three courses of ABVD followed by radiotherapy. Irradiation was performed on extended fields in 41 cases and on involved fields in 53 others. Consolidation chemotherapy was planned in 67 cases with at least one unfavorable prognostic factor, but achieved only in 33 cases. Seventeen patients relapsed within 1 to 46 months after the beginning of treatment. Ten patients died, 7 of HD and 3 of intercurrent diseases or accident. Disease-free survival rate with a median follow-up of 60 months is 80%. This study showed, on the one hand, many digestive and general side-effects after ABVD and, on the other, a satisfactory hematological tolerance. Furthermore, mediastinitis or cardiovascular complications were not more frequent than with MOPP. These results point out the development and use of better tolerated regimens for initial chemotherapy in HD, without jeopardizing the good results of the treatment.

The presentation of Hodgkin's disease (HD) is not the same in western countries and in developing countries. In the latter HD remains a severe disease partly because of a delayed diagnosis. Pathology is less favorable, stages are more advanced. Young patients are even more afflicted. Despite difficulties to treat patients, oncologists have to move to treat as well as possible potentially curable disease in order to save many years of active life. HD would be a good model to promote multidisciplinary centers where patients could be cared and cured in the best conditions.

From 1965 to 1976, 170 patients with Hodgkin's disease, clinical stages I or II, were treated with radical irradiation. A first group of 42 patients was treated with irradiation alone, a second group of 24 patients received one course of chemotherapy followed by irradiation, and a third group of 104 patients was treated with a sandwich regimen including chemotherapy + irradiation + chemotherapy. Although the treatment were not randomized, the comparison of the results shows a striking improvement in the group submitted to the C + R + C regimen: in this group the plateau of disease-free survival was 90 per cent. This result was obtained after treatment for about 3 months without surgical staging or maintenance chemotherapy. However, this treatment may favor some complications,. mainly the development of a second malignancy; these risks may be decreased by reducing the treatment in patients with good prognosis.

A new regimen of chemotherapy was used to reduce toxicity of ABVD: adriamycin is replaced by epirubicin and dacarbazine by prednisone. Thirty eight patients with Hodgkin's disease, stage I to IIIA, previously untreated, received three courses of this regimen before radical radiotherapy. Gastro-intestinal toxicity and alopecia appeared less marked than with ABVD. Immediate efficacy is similar with 80% of complete remission (one third observed at day 28) and only 2 failures. This regimen appears thus as a clear improvement in the treatment of patients with Hodgkin's disease and deserves larger comparison with previously used chemotherapy in a more extensive controlled trial.

Thirty patients aged older than 70 years formed 6.9% of all cases of previously untreated Hodgkin's disease seen in Bordeaux Cancer Center over a 20-year period. The subtype of mixed cellularity was predominant in this age group (P = 0.00035). One patient received no treatment; 20 patients received primary chemotherapy (14 polychemotherapy); all but 2 of the 18 patients in clinical Stages I or II received radical radiotherapy. Median survival for all patients is 15 months. In five cases the treatment could be held responsible for death. Eleven patients died of Hodgkin's disease within a 36-month period. Five patients are alive and the nine other patients died from other causes. The disease-free survival figures showed that one third of the patients could be considered as cured.

The hematologic effects of combined chemotherapy and irradiation were analyzed in 70 patients with Hodgkin's disease stage I and II. The schedule used was as follows: one cycle of 15--21 days of chemotherapy immediately followed by irradiation, including mantle and lumboaortic fields. After a rest of one month, another cycle of the same chemotherapy was applied. The erythrocytes varied slightly; the leukocytes decreased during chemotherapy and were stable or increased slightly during irradiation. Platelets decreased slightly during chemotherapy and more markedly during irradiation. No major side effects were observed, and the regimen appeared well tolerated.

From 1972 to 1976, 102 patients with stages I-IIIA Hodgkin's disease (HD) were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP: two courses) associated with extended field radiotherapy. Staging included neither laparotomy nor splenectomy (clinical staging). Treatment included neither splenic irradiation nor maintenance therapy. Complete remission was achieved for 98 patients and 11 of them recurred up to 94 months after treatment. Median follow-up of this controlled study is 13 years. Disease free survival (DFS) is 87% at 6 years and 84% at 10 and 15 years. Overall survival is 77% at 10 and 74% at 15 years. Disease specific survival is better (91% at 10 and 87% at 15 years) since only 38% (10/26) deaths were due to HD. The other deaths (16/26) with no evidence of HD were due to second cancer and intercurrent disease. Prognostic analysis of DFS by log-rank test gives significance to the following factors: contiguous extra-nodal involvement (P = 0.008), more than 3 involved sites (P = 0.01), signs of compression (P = 0.02), clinical stage IIIA (P = 0.03), infradiaphragmatic stages I-II (P = 0.04). The potential risk of secondary cancer is difficult to assess.

One hundred and fifty patients treated for Hodgkin's disease (stage I to IIIA) in a cooperative trial, answered a questionnaire dealing partly with their information, after 2 to 7 years of complete remission. This information appears insufficient for the majority of patients (52%), at least as far as treatment and its complications are concerned. There are many significant relations with other parameters which suggest that a good level of information may improve quality of life of patients. These observations tend to increase information of patients with Hodgkin's disease, provided it is adapted to each patient.

A new regimen of chemotherapy was used to reduce toxicity of EBVP I: the number of injections and the doses of bleomycin and vinblastine were reduced by half, the duration of treatment by third. Fifty patients with Hodgkin's disease stage I to IIIA, previously untreated, received three courses of this regimen before radiotherapy. Gastro-intestinal toxicity was similar and alopecia was more marked than with EBVP I. Immediate efficacy is similar, with 90% of complete remission and only one failure. This regimen is shorter and more intensive than EBVP I. It deserves larger comparison with previously used chemotherapy in a more extensive controlled trial.

From 1976 to 1981, 335 patients with untreated Hodgkin's disease, clinical stages I, II, and IIIA, have been treated by MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) chemotherapy, three to six cycles according to the prognostic factors, combined with radiotherapy. Irradiation was always performed after the first three cycles of chemotherapy, and was randomized between extensive radiotherapy, ie, mantle and paraaortic areas for supradiaphragmatic presentations, and radiotherapy restricted to the involved areas. No significant difference was observed between the two randomized branches for the disease-free survival (86% after six years in the involved field branch v 90% in the extended field branch), and none for the overall survival. Most of the relapses occurred in nonirradiated areas in the first group, and in irradiated areas in the second. Relapses were especially frequent in the IIE stages with pulmonary extension; extranodal relapses occurred with osseous and cutaneous localizations. Two cases of secondary leukemia were observed after three- or six-cycle MOPP plus radiotherapy limited to the involved areas.

Sixty patients treated for Hodgkin's disease by radio + chemotherapy and remaining in complete remission with a median follow-up of 26 months answered a questionnaire dealing with their quality of life during and after treatment. Their main request was to be better informed about their disease, treatment and its side effects. Therapeutic toxicity is mainly due to chemotherapy and is digestive in nature (nausea and vomiting) symptoms. The majority of patients complained of disturbances in their personal and professional lives. It is concluded that more complete knowledge of all patients' disorders may help doctors to improve treatment planning in order that the patient's quality of life be less disturbed.

We studied the pharmacokinetics and metabolism of epirubicin (4'-epidoxorubicin) in ten patients suffering from Hodgkin's disease and receiving three successive injections of epirubicin at 15-day intervals in a combined chemotherapy regimen. Doses were either constant (35 mg/m2) or escalated from 25 to 35 and 50 mg/m2. Epirubicin metabolism was characterized by the presence of high levels of epirubicin glucuronide in plasma and urine. The area under the time-concentration plasma curve of epirubicin glucuronide reached almost that of unchanged epirubicin (mean ratio = 0.7-0.85), whereas the cumulative urinary excretion of epirubicin glucuronide was one-half of that of epirubicin (mean ratio = 0.45-0.51). Repeating or escalating the doses did not change the levels of the glucuronide significantly. Only a trend towards higher relative levels of glucuronide could be noticed at the lowest dose. The pharmacokinetic parameters of epirubicin were characterized by a high total plasma clearance (mean value: 70-85 1/hr) and a mean elimination half-life of 25-35 hr. Repeating or escalating the doses was followed by a slight increase of the total plasma clearance in most patients, without changes of the elimination half-life. The cumulative urinary excretion was 11-12% of the dose administered and did not vary significantly as a function of time or dose.

One hundred and fifty patients, treated for Hodgkin's disease (stages I-IIIA) in a cooperative trial and remaining in complete remission after 2 to 7 years, answered a questionnaire dealing with psychosocial status and quality of life. Many informations were gathered and studied by multiparametric methods. Quality of life of patients appears determined by three kinds of parameters: patients' characteristics (age, sex, family and work status); stage of the disease determining the intensity and duration of treatment; practical conditions of treatment. These last parameters may be improved by therapeutic team and all care-takers to decrease bad consequences of disease and treatment and also to increase quality of life after cure.

From 1972 to 1976, 95 patients with clinical stages I-IIIA Hodgkin's disease were treated by chemotherapy with cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) before and after extended field radiotherapy. The CVPP schedule gave: (1) a constant drug dosage for each patient independent of body surface or weight; and (2) a total drug dosage dependent on haematological tolerance, since the treatment was given for 21 days or until the leukocyte count dropped to 2 x 10(9) l-1. The drug dosage per unit body surface (or 'dose density') significantly correlates with the drop in leukocyte count (P less than 0.001) and the tumour regression at the end of the induction course (P = 0.020). Disease-free survival is significantly related to dose density (P = 0.050) but not to dose intensity calculated on the duration of treatment (P = 0.240). However, after exclusion of three marginal recurrences due to border-line radiotherapy, the dose intensity significantly correlates with the disease-free survival (P = 0.031) and with the duration of complete remission (r = 0.870).

We have investigated the feasibility of individual dose-monitoring of doxorubicin in lymphoma patients. The purpose was to overcome the large variability of the early-phase kinetic parameters of the drug. We have used a test-dose and calculated for 32 patients a therapeutic dose which could allow us to obtain a predetermined early drug exposure. Such a predetermined drug exposure was obtained in 24 patients of the study. Important variations of the early clearance occurred in 8 patients.