Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial.

Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 µm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 µm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 µm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

Quantification of HBsAg and HBV-DNA during therapy with peginterferon alpha-2b plus lamivudine and peginterferon alpha-2b alone in a German chronic hepatitis B cohort.

BACKGROUND: Peginterferon alpha-2b (PEG-IFNa2b) and lamivudine are efficient treatment options for chronic hepatitis B virus (HBV) infection. We assumed that a combination therapy of PEG-IFNα-2b plus lamivudine will be more effective than PEG-IFNα-2b alone concerning loss of HBV-DNA, HBeAg seroconversion, and HBsAg reduction. PATIENTS AND METHODS: Patients with chronic hepatitis B were randomised to nine months treatment with PEG-IFNα-2b 1.5 µg/kg o. i. w. or PEG- IFNα-2b plus lamivudine 100 mg/d. The study was designed with 60 patients per treatment arm. The primary endpoint was defined as loss of HBV-DNA (< 400 copies/mL) 24 weeks after the end of therapy. HBV-DNA (PCR), HBsAg (Architect, Abbott), and HBeAg (Axsym, Abbott) were determined prior to and at the end of treatment as well as at follow-up. HBV-genotypes were determined by Innolipa (Innogenetics). RESULTS: Only 32 patients were randomised to combination therapy and 27 individuals to monotherapy due to low recruitment rates. On treatment reduction of HBV-DNA was significantly higher during combination therapy compared to PEG-IFNa-2b monotherapy (- 4.60 ± 2.71 vs. - 2.41 ± 2.17 log; p = 0.003). However, there was no difference in the number of cases achieving HBV-DNA < 400 copies/mL, ALT normalisation, or HBeAg seroconversion at follow-up. None of the parameters was significantly related to HBV-genotypes. In a post-hoc analysis serum HBsAg levels were analysed as an additional prognostic parameter for treatment response (n = 29). Combination therapy showed a stronger, but not significant HBsAg decline during (- 0.7 ± 1.17 log IU/mL vs. - 0.26 ± 0.61 log IU/mL; p = 0.35) and after therapy (- 0.68 ± 1.29 log IU/mL vs. - 0.24 ± 0.56 log IU/mL; p = 0.82). Two of three cases with a 2-log HBsAg decline to HBsAg levels < 100 IU/mL eliminated HBsAg during long-term follow-up. CONCLUSION: The study was underpowered with respect to the primary endpoint due to low recruitment rates. However, in the post-hoc analysis HBsAg decline was over two-fold stronger at the end of treatment and follow-up after combination therapy and did not rebound after lamivudine withdrawal. These results may indicate the usefulness of future combination therapies without discontinuation of nucleos(t)ide analogues.

Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases. German Hodgkin's Lymphoma Study Group.

PURPOSE: To describe the incidence of primary bone marrow involvement (BMI) in Hodgkin's disease (HD) and its correlation with clinical and laboratory features present at diagnosis, and to evaluate the prognostic relevance of BMI. PATIENTS AND METHODS: Between 1983 and 1991, 2,307 patients with HD were treated according to two trial generations (HD1-3 and HD4-6) of the German Hodgkin's Lymphoma Study Group (GHSG). RESULTS: One hundred thirty-five cases of primary BMI were observed. The incidence of BMI was 4.8% in the HD4-6 study generation, which included all stages. Among stage IV patients, 32% had BMI. Among those with BMI, other organs were also involved in 33%. Among all patients, the presence of BMI was significantly associated with B symptoms, lymph nodes on both sides of the diaphragm, mixed cellularity histologic subtype, leukocytopenia, anemia, thrombocytopenia, lactate dehydrogenase (LDH) level more than 400 U/L, and erythrocyte sedimentation rate (ESR) more than 40 mm/h. BMI was negatively correlated with a large mediastinal tumor (3.7% v 20.0% in non-BMI cases). Eighty-seven of 108 (81%) assessable patients with BMI achieved a complete remission (CR). This compares favorably with the overall CR rate in all stage IIIB/IV patients. Among stage IV patients, BMI has no prognostic relevance with regard to freedom from treatment failure and overall survival. Twenty-one patients with BMI relapsed after having achieved a CR. Only five of these (24%) again had a positive bone marrow biopsy. CONCLUSION: The prognosis of patients with BMI is not worse than the prognosis of other advanced-stage HD patients. BMI alone does not define a special high-risk group in which a different treatment approach is indicated.

Dexa-BEAM in patients with Hodgkin's disease refractory to multidrug chemotherapy regimens: a trial of the German Hodgkin's Disease Study Group.

PURPOSE: A prospective phase II study was conducted to evaluate the efficacy of dexamethasone, carmustine, etoposide, cytarabine, and melphalan (Dexa-BEAM) as salvage chemotherapy for patients with Hodgkin's disease. PATIENTS AND METHODS: Fifty-five patients progressing on or relapsing after eight- or 10-drug chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisone plus doxorubicin, bleomycin, vinblastine, and dacarbazine [COPP+ABVD] or COPP+ABV+ifosfamide, methotrexate, etoposide, and prednisone [IMEP]) were treated with Dexa-BEAM. Patients who responded after two cycles of Dexa-BEAM either continued treatment for another two to three cycles or received high-dose chemotherapy/autologous bone marrow transplantation (HDCT/ABMT) with cyclophosphamide, etoposide, and carmustine (BCNU) (CVB) as conditioning regimen. RESULTS: Seventeen patients (31%) achieved a complete remission and 16 (29%) a partial remission, resulting in a response rate of 60% (95% confidence interval, 46% to 73%). Progressive disease developed in 18 patients. Toxicity of Dexa-BEAM was acceptable with pronounced, but temporary World Health Organization (WHO) grade III/IV granulocytopenia and thrombocytopenia occurring in more than 90% of all courses. Two patients died of sepsis during granulocytopenia. Three prognostic subgroups could be distinguished: (1) patients progressing on initial chemotherapy, (2) patients relapsing within 12 months, and (3) patients with late relapses. The response rates for these groups were 52%, 60%, and 83%, and the median survival duration 12, 29, and 40+ months, respectively. In a nonrandomized comparison, the survival of patients who responded to two cycles of Dexa-BEAM and had additional cycles of Dexa-BEAM (n = 14) was not different from those responding patients who underwent HDCT/ABMT (n = 19). However, the power to detect a 20% survival difference was only 33% in this comparison. CONCLUSION: Dexa-BEAM is an effective salvage treatment for patients with Hodgkin's disease who fail to respond to multidrug chemotherapy. Efficacy and toxicity are comparable to HDCT/ABMT and underline the need for prospective randomized trials to define better the role of HDCT with and without ABMT in these patients.

Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group.

DESIGN: To perform a meta-analysis of all randomized trials that compared chemotherapy (CT) alone versus combined modality treatment (CT + radiotherapy [RT]) for which individual patient data could be made available. PATIENTS AND METHODS: Data on 1,740 patients treated on 14 different trials that included 16 relevant comparisons have been analysed. Eight comparisons were designed to evaluate the benefit of additional RT after the same CT (CT1 v CT1 + RT; additional RT design). Eight comparisons were designed to evaluate whether RT in a combined modality setting can be substituted by CT using either more cycles of the same CT or regimens that contain additional drugs (CT1 + CT2 v CT1 + RT or CT1 v CT2 + RT; parallel RT/CT design). RESULTS: Additional RT showed an 11% overall improvement in tumor control rate after 10 years (P = .0001; 95% confidence interval [CI], 4% to 18%). No difference could be detected with respect to overall survival (P = .57; 95% CI, -10% to 4%). In contrast, when combined modality treatment was compared with CT alone in the parallel-design trials, no difference could be detected in tumor control rates (P = .43; 95% CI, -6% to 9%), but overall survival was significantly better after 10 years in the group that did not receive RT (P = .045; 8% difference; 95% CI, 1% to 15%). There were significantly fewer fatal events among patients in continuous complete remission (relative risk [RR], 1.73; 95% CI, 1.17 to 2.53; P = .005) if no RT was given. CONCLUSION: Combined modality treatment in patients with advanced-stage Hodgkin's disease overall has a significantly inferior long-term survival outcome than CT alone if CT is given over an appropriate number of cycles. The role of RT in this setting is limited to specific indications.

Low-dose radiation is sufficient for the noninvolved extended-field treatment in favorable early-stage Hodgkin's disease: long-term results of a randomized trial of radiotherapy alone.

PURPOSE: To show that radiotherapy (RT) dose to the noninvolved extended field (EF) can be reduced without loss of efficacy in patients with early-stage Hodgkin's disease (HD). PATIENTS AND METHODS: During 1988 to 1994, pathologically staged patients with stage I or II disease who were without risk factors (large mediastinal mass, extranodal lesions, massive splenic disease, elevated erythrocyte sedimentation rate, or three or more involved areas) were recruited from various centers. All patients received 40 Gy total fractionated dose to the involved field areas but were randomly assigned to receive either 40 Gy (arm A) or 30 Gy (arm B) total fractionated dose for the clinically noninvolved EF. No chemotherapy was given. RT films were prospectively reviewed for protocol violations and recurrences retrospectively related to the applied RT. RESULTS: Of 382 recruited patients, 376 were eligible for randomized comparison, 190 in arm A and 186 in arm B. Complete remission was attained in 98% of patients in each arm. With a median follow-up of 86 months, 7-year relapse-free survival (RFS) rates were 78% (arm A) and 83% (arm B) (P =.093). The upper 95% confidence limit for the possible inferiority of arm B in RFS was 4%. Corresponding overall survival rates were 91% (arm A) and 96% (arm B) (P =.16). The most common causes of death (n = 27) were cardiorespiratory disease/pulmonary embolisms (seven), second malignancy (six), and HD (five). Protocol violation was associated with significantly poorer RFS. Nonirradiated nodes were involved in 42 of 52 reviewed relapses, infield areas in 18, marginal areas in 17, and extranodal sites in 16. CONCLUSION: EF-RT alone attains good survival rates in favorable early-stage HD. The 30-Gy dose is adequate for clinically noninvolved areas. Protocol violation worsens the subsequent prognosis. Relapse patterns suggest that systemic therapy can reduce the 20% long-term relapse rate.

Randomized trial with early-stage Hodgkin's disease testing 30 Gy vs. 40 Gy extended field radiotherapy alone.

PURPOSE: To evaluate whether or not a total dose (TD) of 30 Gy is sufficient for treatment of assumed subclinical Hodgkin's Disease compared to 40 Gy TD with early stage Hodgkin's Disease (ESHD). METHODS AND MATERIALS: In a prospective multicenter trial, 376 patients with laparotomy-proven ESHD stages PS IA to PS IIB without risk factors such as large mediastinum, massive splenic involvement, extranodal disease, elevated erythrocyte sedimentation rate (ESR), and/or three or more involved lymph node areas were randomly allocated either to receive (ARM A) 40 Gy TD extended field-radiotherapy (EF-RT) or (ARM B) 30 Gy TD EF-RT plus 10 Gy TD involved field-radiotherapy (IF-RT), both arms without any chemotherapy. Three hundred sixty-six of these patients were evaluable for early and long-term response, such as remission status, freedom from treatment failure (FFTF), and overall survival (OAS). For quality control, all planning and verification films as well as dose charts were prospectively reviewed by a panel of four experts, all heads of a radiotherapy department, where protocol violations (PV) were seen either with regard to errors in treatment technique, treatment volume, in TD and/or in dose/time-relationship. RESULTS: Treatment resulted in a complete remission (CR) of 98%; in a 5-year FFTF of 76%, and a 5-year OAS of 97%. There was no difference between the two arms in favor of 40 Gy EF compared to 30 Gy EF regarding FFTF and OAS, without any in field relapse throughout the EF volumes. Expectedly, 5-years FFTF was significantly influenced by the quality of radiotherapeutical procedures: 70% with protocol violations (PV) vs. 82% without PV. CONCLUSION: Subclinical involvement in ESHD without risk factors is sufficiently treated by a TD of 30 Gy without chemotherapy, leading to a 5-years FFTF of 82% and a 5-year OAS of 97% in a multicenter treatment setting, where quality assurance is mandatory.

Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin's disease.

Chemotherapy-treated patients with advanced Hodgkin's disease (HD) differ considerably in acute hematotoxicity. Hematotoxicity may be indicative of pharmacological and metabolic heterogeneity. We hypothesized that low hematotoxicity might correlate with reduced systemic dose and thus reduced disease control. A total of 266 patients with advanced HD treated with cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD) were analyzed (HD6 trial of the German Hodgkin's Lymphoma Study Group). The reported WHO grade of leukocytopenia was averaged over chemotherapy cycles given and weighted with the reciprocal dose intensity of the corresponding cycle. The low and high toxicity groups were defined in retrospect as having had an averaged WHO grade of leukocytopenia 2.1, respectively. The independent impact of low hematological toxicity on freedom from treatment failure (FFTF) was assessed multivariately adjusting for the international prognostic score for advanced HD. The results were validated in two independent cohorts [181 patients treated with COPP-ABVD (HD9-trial) and 250 patients treated with COPP-ABV-ifosfamide, methotrexate, etoposide, and prednisone (IMEP) (HD6 trial)]. The 5-year FFTF rates were 68% for patients with high toxicity vs 47% for patients with low toxicity [multivariate relative risk (RR) 2.0, 95% confidence interval (CI) 1.4-3.0, p=0.0002]. Patients with low toxicity received significantly higher nominal dose ( p=0.02) and dose intensity ( p<0.0001). This finding was confirmed in both validation cohorts (multivariate RR 2.1, 95% CI 1.2-3.8, p=0.01 and RR 1.5, 95% CI 1.01-2.26, p=0.04, respectively). Patients with low hematotoxicity have significantly higher failure rates despite higher doses and dose intensity. Hematotoxicity is an independent prognostic factor for treatment outcome. This observation suggests a strategy of individualized dosing adapted to hematotoxicity.

Patterns of spontaneous motility in videomicrographs of human epidermal keratinocytes (HEK).

The subject of our observations was the spontaneous behaviour of normal and transfected human epidermal keratinocytes. Cell movements were recorded on video micrographs and analyzed by a mathematical approach, using new methods of image processing and statistical correlation analysis. Protrusive activity of single lamellae was examined using one-dimensional analysis of phase-contrast image sequences along section lines transversal to the cell edge. This method revealed high periodicity and correlation in the motility patterns of lamellae and ruffles. Two-dimensional correlation analysis of automatically digitized cell outlines was applied to detect spatiotemporal patterns and coordination of lamellar extension and retraction. Most cells showed regularly alternating pulsations of lamellar protrusions. In some extreme cases, extension waves rotating around the cell periphery were observed. The results were compared with computer simulations of two simple models for lamellar dynamics and shape deformation, based on few assumptions about chemical kinetics of F-actin and cytomechanical properties of the actin network, neglecting regulatory effects of actin-associated proteins or extracellular stimulations. The simulation results reproduced the main dynamical features of the observed real cells, indicating the possibility that the basic universal mechanism for lateral coordination of lamellipodial protrusion is the interplay between hydrostatic pressure and viscocontractile tension in the cortical F-actin-plasma membrane complex.

Modelling of chemotherapy: the effective dose approach.

We sketch the development of the effective dose approach which provides a theoretical framework to interpret chemotherapy outcome data. Building on the generalised Skipper model of chemotherapy, a meta-regression method is derived to jointly analyse all chemotherapy comparing randomised clinical trials in a given malignancy in order to explore the slope of the effective dose/outcome relationship and the relative potency of cytostatic drugs. The model is applied to explain why treatment differences in aggressive NHL appear to differ by risk groups in aggressive NHL. A respective meta-subgroup analysis to confirm this interaction hypothesis is proposed.

The clinical significance of serum CD8 antigen levels in adult patients with Hodgkin's disease.

Increased suppressor T-cell activity has been observed in patients with Hodgkin's disease. In order to evaluate the clinical significance of soluble CD8 antigen (sCD8), which is released from CD8+ suppressor/cytotoxic T-lymphocytes, we determined sCD8 levels in the sera of 82 consecutive patients with newly diagnosed untreated Hodgkin's lymphoma who were entered into prospective trials of the German Hodgkin's Disease Study Group. sCD8 levels were significantly higher (p less than 0.01) in stage IV (781 U/ml, n = 19) than in stages I-IIIB (443 U/ml; n = 63). Patients with B-symptoms (n = 36) had slightly higher levels (611 U/ml) than patients without (n = 46) systemic symptoms (447 U/ml; p = 0.08). In 77 patients evaluable for response, the complete remission (CR) rate of patients with sCD8 less than 750 U/ml was higher (54/60 or 90%) than that of patients with sCD8 greater than 750 U/ml 11/17 or 65%; p = 0.01). The time to treatment failure was significantly longer in patients with sCD8 less than 750 U/ml (p = 0.008), even among the group with stages IIIB/IV only (p = 0.04). Our data suggest that the pretreatment levels of sCD8 in adult patients with Hodgkin's lymphoma have prognostic relevance, and that they should be determined especially in patients with advanced disease. Increased understanding of the role of sCD8 may shed light on the pathogenesis of Hodgkin's disease.

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.

The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies.

Today it is possible to cure more than 90 % of children and adolescents with Hodgkin's disease with a combination of radiotherapy and chemotherapy. Since the DAL-HD 82 study, the main scientific focus has been on avoiding late effects such as the OPSI syndrome, late complications involving the heart, lungs, thyroid and/or gonads particularly sterility in men and premature onset of menopause in women, and the prevention of secondary malignancies. The GPOH-HD 2003 study will introduce FDG-PET to the initial diagnostic program and the assessment of response to therapy in order to evaluate further possibilities for reducing therapy. In this context, the central review of all clinical and radiological findings, systematically done since the DAL-HD 90 study, will be increasingly relevant in maintaining standardised stage classification and therapy group assignment which was established by the preceding studies. Continuing in the direction of the earlier studies, the indications for radiotherapy will be restricted even further. In the early stages (treatment group 1) patients with CR or a negative FDG-PET at the end of chemotherapy will receive no radiotherapy in order to reduce the risk of a secondary malignancy. In a randomized comparison, procarbazine will be replaced by dacarbazine in the COPP cycles to determine whether sterility in men and premature onset of menopause in women can be avoided by elimination of procarbazine while retaining the same clinical efficacy. Finally, relapse therapy is to be tailored according to the time of relapse, the initial therapy group, and the patient's response to the relapse therapy with more patients receiving autologous transplantation in order to further improve the results of relapse treatment.

Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.