A population-based cohort study on early-stage Hodgkin lymphoma treated with radiotherapy alone: with special reference to older patients.

BACKGROUND: Combined modality treatment has reduced the risk of relapse among younger early-stage Hodgkin lymphoma (HL) patients. Older HL patients may not tolerate chemotherapy and their prognosis is less favorable. We conducted a population-based study to evaluate long-term follow-up outcome in older early-stage HL patients initially treated with radiotherapy (RT) alone. PATIENTS AND METHODS: We included 308 consecutive patients (22% were >or=60 years) diagnosed 1972-1999 (median follow-up 20 years; range 1-28). Using Cox regression models we defined risk of relapse and survival in relation to clinical factors. RESULTS: 272/308 (88%) patients obtained complete remission following first-line RT alone. Among these, 42% relapsed within a median of 21 months. The relapse rate was independent of gender and age at diagnosis (median age 32 years, range 14-85); however, lymphocyte-predominant HL was associated with borderline (P=0.049) 56% decreased risk of relapse. Among patients<60 years and >or=60 years, we observed 29 (median latency 10 years, range 2-25) and 11 (median latency 3 years, range 1-10) second tumors, respectively. CONCLUSIONS: Older age (>or=60 years) was not associated with an increased risk of relapse following RT alone. Given the risks of iatrogenic morbidity/mortality of chemotherapy in older patients, RT alone could be an alternative first-line therapy in early-stage older HL patients.

Determinants of health-related quality of life in long-term survivors of Hodgkin's lymphoma.

In this study health-related quality of life (HRQL) in long-term survivors of Hodgkin's lymphoma (HL) was evaluated and the findings were analyzed using a conceptual model developed by Wilson and Cleary. A better understanding of the relationships between the variables explaining HRQL may improve care and rehabilitation of HL patients. The populations were long-term survivors of HL (n = 121) and a control group (n = 236). Participants were approached with one semi-structured interview, an extended version of the Schedule for the Evaluation of Individual Quality of Life - Direct Weighting (SEIQoL-DW) and three standardized questionnaires: Hospital Anxiety and Depression (HAD) scale, Short Form 12 health survey questionnaire (SF-12) and Sense of Coherence (SOC) scale. No differences regarding the mean scores were found between the HL survivors and the controls except for the SF-12, where the patients considered themselves to be in poorer physical health than the controls (p < 0.01). Even though physical health was diminished, patients did not evaluate overall QoL worse compared to the controls. The major determinants of perception of general QoL were self-rated physical and mental health as well as SOC. The HRQL of persons who have survived a median of 14 years with HL is similar to that of controls.

A prospective study on antibody response to repeated vaccinations with pneumococcal capsular polysaccharide in splenectomized individuals with special reference to Hodgkin's lymphoma.

BACKGROUND: Splenectomy is accompanied by a life-long risk of overwhelming postsplenectomy infection (OPSI), mainly caused by polysaccharide (PS) encapsulated bacteria such as Streptococcus pneumoniae. Despite extensive prophylactic efforts the mortality and morbidity rates remain high. The present study was based on a strategy with a predefined vaccination algorithm including repeated 23-valent pneumococcal vaccinations and monitoring of pneumococcal antibody levels. The antibody levels of splenectomized Hodgkin's lymphoma (HL) patients were compared with those patients splenectomized due to immune-mediated cytopenias [autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP)] and also individuals who were splenectomized because of trauma (TRAUMA). METHODS: A total of 311 splenectomized individuals were included in this prospective study (208 HL; 15 AIHA; 60 ITP; 28 TRAUMA). Depending on their individual anti-PS antibody levels measured by enzyme-linked immunosorbent assay technique the patients were revaccinated with 23-valent pneumococcal PS vaccine up to four times in accordance with the predefined algorithm. For each vaccination occasion, serum was collected at vaccination, after 1 month +/- 2 weeks (peak), and after 1 year +/- 6 months (follow-up). Patient files, a national population-based database, and microbiological databases were checked for 124 HL patients to identify OPSI. RESULTS: A significant response was recorded on primary vaccination as well as on two revaccination occasions for HL, AIHA/ITP, as well as TRAUMA patients. None of the variables age, gender, or time elapsed between splenectomy and first pneumococcal vaccination was found to be associated with mean PS antibody levels at prevaccination, peak or follow-up. No severe adverse events were reported. Amongst 124 clinically monitored HL patients, 10 OPSI were recorded in seven patients during the study period. One of these patients, a middle-aged female, died as a result of fulminant pneumococcal bacteraemia, which was her third OPSI during a 7-year period. CONCLUSIONS: A significant response to pneumococcal PS vaccination was found in all three groups (HL, AIHA/ITP and TRAUMA) of splenectomized patients. Importantly, both primary and repeated vaccinations were safe. Until further knowledge is gained regarding the protective concentration of serotype-specific antibody concentrations we believe that the value of vaccination and frequent revaccination (every 1-5 years) in combination with education of patients and health care professionals and clinical monitoring is beneficial for these patients at risk for OPSI.

Individual quality of life in long-term survivors of Hodgkin's lymphoma--a comparative study.

This study aimed to use an individual approach in evaluating QoL in long-term survivors of Hodgkin's lymphoma (HL) and their view of what impact the disease has had on life using an extended version of the The Schedule for the Evaluation of the Individual quality of life-Direct Weighting (SEIQoL-DW). Adult long-term survivors from HL (n = 121) were compared with a randomly selected sample of the general population in Stockholm (n = 236). The results showed that the most commonly nominated areas (> 50% of patients and controls) important in life were family, personal health, work and relations to other people. The HL survivors mentioned leisure and finances less frequently than the controls. However, neither the current status in the different areas nor the QoL index score differed between survivors and controls. Thoughts and worries around disease, fatigue and loss of energy and late effects on skin and mucous membrane were the most commonly reported problems following HL. Sixty-six percent of the survivors reported a change in their view of life and of themselves. Demographic and disease characteristics did not influence the ratings of the chosen areas. In conclusion, long-term survivors of HL seem to have adapted well to the situation of having had a life-threatening disease and undergoing treatment, as measured with SEIQoL-DW. The extended Swedish version with a disease-specific module could be of great value when identifying specific issues that are important for the patient at time of evaluation.

Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity?

BACKGROUND: Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy. PATIENTS AND METHODS: The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions. RESULTS: The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity. DISCUSSION: More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome. CONCLUSION: ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.

Tissue eosinophilia in relation to immunopathological and clinical characteristics in Hodgkin's disease.

Eosinophils frequently infiltrate tissues involved by Hodgkin's disease (HD), and blood eosinophilia is frequently observed. However, the clinical significance and the mechanisms underlying eosinophilia need further elucidation. In this study the grade of eosinophilic infiltration (EoI) was evaluated in biopsies from 259 HD-patients. In a selected group (n=32), the numbers of Hodgkin-Reed-Sternberg (HRS)-cells were counted, and the phenotype of small lymphocytes, the expression of cytotoxic lymphocyte-associated proteins, CD3-zeta-chain, HLA-DR, proliferation markers, latent membrane protein 1 (LMP-1) and blood lymphocyte function were evaluated. Samples from 88 HD patients (34%) showed high EoI. Significantly higher EoI was seen in nodular sclerosis 2 (NS2; p<0.001), bulky disease (p<0.05) and in patients <50 years (p<0.05). Patients with high EoI did not differ from the remainder with regard to distribution of sex, stage, B-symptoms, blood lymphocyte function and outcome. HRS-cells were significantly more frequent in NS HD as compared to mixed cellularity (MC) (p<0.001) irrespective of EoI. LMP-1-expression, proliferative fraction and phenotypes of small lymphocytes did not differ between the cases with low and high EoI, respectively. MC HD samples had significantly higher numbers of small cells positive for CD8 (p<0.01), T-cell intracellular antigen-1 (p<0.01) and Granzyme B (p<0.05) than NS. LMP-1-positive cases had significantly higher frequency of CD8-positive cells than LMP-1-negative. In conclusion, high EoI remains a feature of certain clinical subgroups of HD. However, there was no association between the degree of EoI and numbers of HRS-cells, phenotypes of small lymphocytes, EBV status and clinical outcome. Determination of EoI is of limited diagnostic and prognostic clinical value in HD. However, the differences in small cell distribution of CD8, TIA-1, GrB and CD57 between the histopathological groups and between LMP-1-expressing/non-expressing cases may contribute to our understanding of the biology of the disease.

Routine bone scintigraphy is of limited value in the clinical assessment of untreated patients with Hodgkin's disease.

The aim of this retrospective study was to evaluate the role of routinely performed bone scintigraphy in the clinical assessment of patients with previously untreated Hodgkin's disease (HD). One-hundred and eighty-three patients with a median age of 31 yrs (range 16-85) with newly diagnosed HD underwent bone scintigraphy between 1972 and 1995. Bone scintigraphies and skeletal X-ray examinations of patients with any pathological scintigraphic finding were reassessed. Initially HD bone involvement could be excluded in 173 (95%) of the patients. Among the remaining ten patients, two had diffuse increased tracer uptake but X-rays were normal. One of these patients was classified as normal with regard to HD bone involvement. A bone marrow scintigraphy examination and regression of changes following therapy supported primary osseous involvement in the other patient. Five patients had focal scintigraphic abnormalities but skeletal X-rays remained negative; three of these five patients reported pain in the scintigraphically affected areas, and therefore the suspicion of bone involvement was strong. The remaining three patients had focal findings both on bone scintigraphy and skeletal X-ray examination and were considered as having osseous HD involvement. All seven patients judged to have HD bone involvement were planned to receive combination chemotherapy up-front, irrespective of the scintigraphic findings. In this series of 183 patients bone involvement was detected in seven patients based on bone scintigraphy/symptoms (n=3), bone marrow scintigraphy/symptoms (n=1), and bone scintigraphy/X-ray examination (n=3). The decision to give multiagent chemotherapy to all patients was not influenced by scintigraphic findings. Therefore, routine bone scintigraphy seems to be of limited value in the clinical assessment of untreated patients with HD.

Biological markers may add to prediction of outcome achieved by the International Prognostic Score in Hodgkin's disease.

BACKGROUND: The International Prognostic Score (IPS) identifies seven independent factors predicting progression-free and overall survival in advanced stage Hodgkin's disease (HD). The IPS is also applicable in limited disease. However, the IPS does not identify patients with a very poor prognosis. The aim of this study was to define biological markers which may add to the IPS in predicting outcome. PATIENTS AND METHODS: One hundred forty-five patients (> 15 years) with HD of all stages and histopathology subgroups were included. In addition to factors included in the IPS, serum levels of CRP, sCD4, sCD8, sCD25, sCD30, sCD54, interleukin (IL)-10, beta2-microglobulin and thymidine kinase were analysed. RESULTS: The strongest predictors of a poor cause-specific survival (CSS) in univariate analyses were: increased serum levels of IL-10, sCD30 and CRP, anaemia, low levels of albumin (P < 0.001); stage IV (P = 0.003), age > or = 45 years (P = 0.006), increased serum levels of sCD25 (P = 0.010), low lymphocyte counts (P = 0.020). Serum IL-10 added prognostic information to that achieved by the IPS: patients with a high score and increased serum IL-10 had a very poor outcome with a five-year CSS of 38%. Patients with increased serum levels of sCD30 and a high score also had a poor outcome with a five-year CSS of 54%. CONCLUSION: Serum levels of IL-10 and sCD30 may add to IPS in prediction of outcome in HD, and should be validated in large, prospective studies.

Epstein-Barr virus expression in Hodgkin's disease in relation to patient characteristics, serum factors and blood lymphocyte function.

Epstein-Barr virus (EBV) expression was investigated by immunohistochemistry (latent membrane protein 1 [LMP-1]) and in situ hybridization (EBV encoded RNA [EBER]) in biopsies from 95 patients with untreated Hodgkin's disease (HD). Tumour EBV status was related to EBV antibody titres, spontaneous and concanavalin A induced blood lymphocyte DNA synthesis, serum levels of soluble (s) CD4, sCD8, sCD25, sCD30, sCD54, beta2-microglobulin, thymidine-kinase, routine chemistry, patient characteristics, complete remission and survival. The median follow-up time was 145 months (range 60-257). Tumour EBV-positive (n = 30; 33%) and negative (n = 62; 67%) patients did not differ with regard to sex, age, stage, presence of bulky disease or B-symptoms, remission rate or survival. The proportion of EBV+ cases was significantly higher among patients with mixed cellularity histopathology (58%) as compared to the nodular sclerosis subtype (18%; P < 0.001). The total white blood cell (WBC) counts were significantly lower in EBV+ patients (P < 0.01), who also had significantly higher levels of sCD54 (P < 0.02) and a tendency towards lower levels of sCD30 (P = 0.056). Patients in the tumour EBV+ group had significantly higher IgG antibody titres to restricted early antigen (EA-R) (P < 0.02). Hence, clinical features and outcome were not related to tumour EBV status. However, HD patients with EBV+ tumours had elevated sCD54 levels, higher antibody titres to EA-R and decreased total WBC counts. A potential causal relationship between EBV tumour status and these findings needs to be further explored.

Tumour necrosis factor-alpha cytokine promoter gene polymorphism in Hodgkin's disease and chronic lymphocytic leukaemia.

Regulation of cytokine levels has been shown to be under genetic control through the coding and promoter sequences of genetic polymorphisms. We elucidated the prevalence of a previously described G to A transition polymorphism at position -308 of the tumour necrosis factor-alpha (TNF-alpha) promoter region in a population of patients with Hodgkin's disease (HD) (n = 36) and chronic lymphocytic leukaemia (CLL) (n = 49) and healthy volunteers (n = 51). The DNA fragment containing this polymorphism was amplified by PCR and sequenced by solid-phase minisequencing. The frequency of the TNF-alpha promoter polymorphism was not significantly different between CLL patients and HD patients compared to controls.

Fixed versus response-adapted MOPP/ABVD chemotherapy in Hodgkin's disease. A prospective randomized trial.

BACKGROUND: The optimal number of chemotherapy courses in responding patients with advanced-stage Hodgkin's disease (HD) is unknown. PATIENTS AND METHODS: With minimizing chemotherapy and thereby reducing late complications as the objective, patients with advanced HD were randomized to receive either 4 full MOPP/ABVD courses or treatment up to complete remission (CR). Forty-seven patients were given the fixed (FT) and 41 patients the individual treatment (IT). The two groups were balanced according to age, histopathology and sex, although stage IVB dominated in the IT group (20 vs. 8). RESULTS: Sixty-six of 88 patients (75%) achieved CR. No difference between the two treatment groups in the proportion of stage IVB patients was seen when those achieving CR, i.e., the efficacy population were compared. The mean number of single chemotherapy courses given was 3.7 of MOPP and 3.5 of ABVD in the FT group, compared to 2.6 of MOPP and 2.5 of ABVD in the IT group (p < 0.001). The predicted progression-free survival at 10 years was 81% in the FT and 68% on the IT arm, respectively (p < 0.05). No statistically significant difference in cause-specific 10 year survival was observed (82% and 83%, respectively; p = 0.18). Long-standing CRs were achieved following minimal chemotherapy. CONCLUSIONS: Since there are no available methods to identify long-term disease-free survivors among CR patients following a limited induction treatment, we suggest that the policy of giving 3-4 full MOPP/ABVD courses should continue. The price for such an approach is the overtreatment of a subset of already cured patients.

Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia.

OBJECTIVE: To assess leucocyte doubling time (LDT) in relation to progression-free survival in patients with chronic lymphocytic leukaemia (CLL). In addition, to define the impact of a second LDT in both untreated and treated patients. DESIGN: Retrospective study of LDT in previously untreated patients with CLL. SUBJECTS AND SETTING: Sixty patients diagnosed over a 13-year period at a county hospital. In forty-five of the 60 patients, an LDT could be defined. These patients were included in the final analysis. MAIN OUTCOME MEASURES: LDT below and above 12 months, progression-free and overall survival. RESULTS: Patients in Binet stages B and C had a median LDT of 4 months as compared to 26 months in stage A patients (P < 0.01). The projected progression-free survival at 3 years was 24% in patients with an LDT of < 12 months. The corresponding figure for the remaining patients was 68% (P < 0.01). The overall 5-year survival did not differ significantly between patients with an LDT below and above 12 months, respectively. In seven untreated patients, a second LDT could be calculated which was shorter than the first recorded LDT. A second LDT was also identified in five patients post treatment that was consistently shorter than their first LDT. CONCLUSIONS: Measurement of LDT is a simple complement in predicting progression-free survival in patients with CLL. Thus, monitoring of LDT may add to the clinical evaluation and therapeutic decision making for the many elderly patients with this often indolent disease.

Monitoring of hearing during treatment of leukaemia with special reference to the use of amikacin.

Thirty-nine patients with leukaemia were followed audiometrically during treatment with broad-spectrum antibiotics. Amikacin was given during neutropenic febrile episodes. Five patients reported a deterioration of the hearing function after termination of amikacin treatment. Significant hearing threshold loss occurred in 20 patients (51%). The hearing threshold changes were small in general, except for two patients who exhibited bilateral hearing threshold changes in the frequency range 0.5-8 kHz. Using multiple linear regression analysis 22% of the changes in hearing thresholds was estimated to be related to old age, an increased trough concentration of amikacin and an impaired pretreatment hearing state. Factors found not to influence the hearing thresholds were maximum peak concentration of amikacin, cumulative duration of therapy, pretreatment renal dysfunction and concomitant use of vancomycin. It is concluded that administration of amikacin for repeated treatment courses is associated with a low incidence of serious changes in hearing function.