No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy.

When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.

Long-term risk of cardiovascular disease in Hodgkin lymphoma survivors--retrospective cohort analyses and a concept for prospective intervention.

Previous studies have shown increased cardiovascular mortality as late side effects in Hodgkin lymphoma (HL) patients. This study identifies stratifying risk factors for surveillance and defines concepts for a clinical feasible and noninvasive prospective protocol for intervention of cardiovascular side effects. HL patients diagnosed between 1965 and 1995 (n = 6.946) and their first-degree relatives (FDR) were identified through the Swedish Cancer Registry and the Swedish Multigeneration Registry. For the HL and FDR cohort, in-patient care for cardiovascular disease (CVD) was registered through the Hospital Discharge Registry, Sweden. Standard incidence ratios of developing CVD for the HL cohort were calculated. A markedly increased risk for in-patient care of CVD was observed in HL patients with HL diagnosed at age 40 years or younger and with more than 10 years follow-up. In the HL survivors, a family history of congestive heart failure (CHF) and coronary artery disease (CAD) increased the risk for these diseases. The Swedish Hodgkin Intervention and Prevention study started in 2007. In the pilot feasibility study for prospective intervention (47 patients), about 25% of the cases had side effects and laboratory abnormalities. These patients were referred to a cardiologist or general practitioner. In the prospective cohort, a positive family history for CHF or CAD could be a stratifying risk factor when setting up a surveillance model. The prospective on-going study presents an intervention model that screens and treats for comorbidity factors. This article also presents an overview of the study concept.

FDG-PET in the detection of residual disease and relapse in patients with Hodgkin's lymphoma. Experience from a Swedish centre.

The aim of this retrospective study was to compare the value of FDG-PET with conventional imaging in patients with residual disease or suspected relapse in Hodgkin's lymphoma (HL). We reviewed the records of all patients with HL who were referred for FDG-PET at our PET centre between April 2002 and August 2004. Thirty-four FDG-PET scans performed on 26 patients were included in the study. Referrals were based on either the presence of a residual mass on computed tomography (CT) (n = 13) or suspicion of relapse (n = 21). We found one false negative and one false positive FDG-PET scan. The high positive predictive value of FDG-PET in the residual group and the high negative predictive value in the relapse group strongly indicate that FDG-PET has an important role to play in the management of HL.

Scalp hypothermia to prevent chemotherapy-induced alopecia is effective and safe: a pilot study of a new digitized scalp-cooling system used in 74 patients.

GOALS: The aim of this study was to examine the efficacy and safety of a new digitized, controlled, scalp-cooling system to prevent chemotherapy-induced alopecia. METHOD: Seventy-four female cancer patients who received 13 varying chemotherapy regimens were included in a nonrandomized pilot study. The Digni 2-3 with Dignicap system consists of a refrigerator unit and a control unit integrated into a mobile cabinet and connected to a tight-fitting cooling cap. This system maintains a constant scalp temperature of +5 degrees C for many hours. In this study, 60 patients were treated for ovarian cancer with either taxane or epirubicin combination chemotherapy. Eight patients with Hodgkin's lymphoma, three with breast cancer, two with endometrial cancer, and one with sarcoma were also included. Photo documentation and patient assessment of hair loss and discomfort were performed. RESULTS: In anthracycline-treated patients, total prevention of hair loss was observed, whereas hair loss in paclitaxel/docetaxel-treated patients was minimal to none. The combination of anthracycline and taxane resulted in more hair loss, but only three of six patients used a wig. Scalp cooling was generally very well tolerated; only two of 74 patients discontinued use of the cold cap due to discomfort. No scalp metastases occurred over a median follow-up period of 15 months. CONCLUSIONS: The digitized, controlled, scalp-cooling system represents an effective and safe device that should be clinically evaluated in a randomized trial and in studies using other chemotherapy regimens to determine optimal temperatures and durations of cooling for maximal efficacy.

Patients above sixty years of age with Hodgkin's lymphoma treated with a new strategy.

In the Swedish National Care Programme for Hodgkin's lymphoma (HL) a less intensive chemotherapy regimen with individualized dosing (LVPP/OEPA) was introduced in 1989. In total, 139 patients, 77 between 1985 and 1988 and 62 between 1989 and 1992, were studied. Mean ages were 72 and 71 years, respectively. One hundred and nineteen patients were treated with curative intention, 63 (82%) between 1985 and 1988 vs. 56 (90%) between 1989 and 1992 (p = 0.11). All patients (13 vs. 20) treated with radiotherapy only achieved a complete remission (CR). The CR rates (67% vs. 65%) for patients treated with 6-8 cycles of chemotherapy were also similar in the two time periods. The 5-year survival rate was 45% in the period 1985-1988 and 48% in 1989-1992. The survival of elderly HL patients was thus not improved from 1985-1988 to 1989-1992. Thus efforts to improve the chemotherapy regimen with individualized dosing did not change the outcome. Many patients experienced myelosuppression and opportunistic infections that may have contributed to the poor treatment results.

A systematic overview of radiation therapy effects in Hodgkin's lymphoma.

A systematic review of radiation therapy trials in several tumour types was carried out by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for Hodgkin's lymphoma (HL) is based on data from 12 randomized trials and 2 meta-analyses. Data from 3 prospective studies, 29 retrospective studies and 58 other articles were also used. In total, 58 scientific articles are included, involving 27,280 patients. The results were compared with those of a similar overview from 1996 including 38,362 patients. The conclusions reached can be summarized thus: Solid scientific documentation shows that in patients with HL more than 80% in the early stages and 60-70% of younger patients in advanced stages of disease are now cured by the development of radiotherapy and combination chemotherapy. Long-term follow-up shows that after 15 to 20 years the mortality from HL in early and intermediate stages is exceeded by other causes of death, mostly secondary malignancies and cardiac deaths, especially myocardial infarction. Convincing data show that radiotherapy plays a major role in the development of solid cancers and cardiovascular disease, but no randomized trials have been performed. During the past decade increasing awareness of fatal long-term sequelae has fundamentally changed treatment strategies in early and intermediate stages. A thorough long-term follow-up is essential to evaluate the effects of the modifications of the therapy. In early stages of disease extended field irradiation is now replaced by short periods of chemotherapy followed by limited radiotherapy to decrease late sequelae. This approach is strongly supported by early reports from randomized trials. Final results cannot be fully evaluated for many years. The optimal radiation dose and volume after chemotherapy are not defined or if irradiation is needed at all. Several studies are under way. In intermediate stages two recently reported randomized trials indicate that combined modality therapy is preferable and that involved field could replace extended field irradiation. It is still too early to draw any firm conclusions. In advanced stages, there is no evidence of any survival benefit from additional radiotherapy. The role of radiotherapy in the case of residual tumour and bulky disease still remains controversial. There is no scientific support for improved survival with radiotherapy in conjunction with high-dose chemotherapy with stem-cell support. Radiotherapy as salvage treatment might be an alternative in late limited nodal recurrence after initial chemotherapy. However, the body of knowledge is small. The role of radiotherapy in the treatment of HL is decreasing.

A systematic overview of radiation therapy effects in non-Hodgkin's lymphoma.

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for non-Hodgkin's lymphoma (NHL) is based on data from seven randomized trials. Moreover, data from 17 prospective studies, 22 retrospective studies and 27 other articles were used. In total, 73 scientific articles are included, involving 13,305 patients. The results were compared with those of a similar overview from 1996 including 14,137 patients. The conclusions reached can be summarized as follows: Indolent lymphomas. Data indicate that one-third to one-half of patients with indolent lymphoma in stage I are cured by radiotherapy (follow-up more than 15 years). Addition of chemotherapy to radiotherapy does not indicate any improvement in overall outcome. Optimal radiation dose is not defined and extended field is not superior to involved field. Aggressive localized lymphomas. Data indicate that half of the patients in stage I are cured by radiotherapy alone. Although randomized and non-randomized studies favour combined modality treatment with chemotherapy followed by radiotherapy instead of radiotherapy or chemotherapy alone in localized disease, no firm conclusions can be drawn. Conflicting data have been published on the value of radiotherapy towards bulky disease and no firm conclusions can be drawn. Optimal dose for radiation alone or after chemotherapy has not been established. Total body irradiation (TBI). The value of TBI for treatment of NHL has not been proven. There is no proof that fractionated TBI in conjunction with high-dose chemotherapy is superior to chemotherapy regimens alone. Primary CNS lymphomas. Data show that radiotherapy induces a response of short duration and is associated with major neurotoxicity, especially in elderly patients. High-dose methotrexate therapy seems to lead to longer survival than radiotherapy alone. No randomized trials have been performed. There is fairly good support for primary chemotherapy including high-dose methotrexate followed by radiotherapy in patients below 60 years. To minimize the risk of neurotoxicity of combined modality treatment it has been proposed to use chemotherapy alone and delay radiotherapy for relapse, especially in patients above 60 years, or use it in chemotherapy-resistant disease. Optimal chemotherapy regimen is not defined and the role of radiotherapy remains to be determined. Head and neck lymphomas. There is some support for combined modality treatment with chemotherapy and radiotherapy for aggressive lymphomas in Waldeyer's ring with limited disease. There are sparse data supporting radiotherapy alone in localized indolent lymphomas in salivary glands. Radioimmunotherapy (RIT). Radioimmunotherapy is a new treatment modality with systemic radiation for patients with advanced NHL, where conventional external beam radiotherapy plays only a minor role. Several phase I and II studies with RIT have documented promising results. A variety of monoclonal antibodies, radionuclides and study designs with both myeloablative and non-myeloablative approach have resulted in high response rates in patients with recurrent or refractory NHL. One randomized clinical trial is published, showing superior therapy results with radiolabelled antibody compared with the corresponding unlabelled antibody.

Early and intermediate stage Hodgkin's lymphoma--report from the Swedish National Care Programme.

In Sweden a National Care Programme provides treatment principles for Hodgkin's lymphoma (HL) since 1985, for early and intermediate stages often less extensive than international recommendations. The purpose is to evaluate long-term results of these principles. A total of 308 patients (167 men and 141 women), 17-59 yr old (median 31), diagnosed during 1985-92, pathological stage (PS) I-III1A and I-IIB and clinical stage (CS) I-IIA, mean follow-up 8.8 yr, were studied. Staging laparotomy was recommended in CS IIA. Recommended treatment was mantle or mini-mantle radiotherapy (RT) alone in CS IA, and PS I-IIA and subtotal nodal irradiation in PS III1A if the disease was not bulky. Patients in PS I-IIA and III1A with bulky disease, and PS I-IIB received one cycle of mechlorethamine, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, vinblastine, lacarbazine (MOPP/ABVD) before irradiation. The remaining patients received three to four cycles of MOPP/ABVD with RT to bulky disease. Relapse-free (RFS), Hodgkin specific (HLS), and overall survival (OS) at 10 yr were 74%, 92% and 85%. In the individual stages, RFS ranged from 53% (PSIII1A) to 90% (PS IA). RFS (P = 0.006), HLS, and OS were significantly better in patients treated with chemotherapy compared with those treated with RT alone, especially in patients with bulky disease (P = 0.0005). The international prognostic score did not provide any prognostic information. The OS rates are in agreement with results from international centres during that time. The recommended treatment was sufficient to produce the desired results of <20-30% recurrences, except in PS III1A. Most relapses could be salvaged. Patients with risk factors treated with one MOPP/ABVD and RT had an excellent outcome, superior to those without risk factors treated with RT alone. These results favour the trend to treat early and intermediate stages with a short course of chemotherapy followed by limited RT.

Bulky disease is the most important prognostic factor in Hodgkin lymphoma stage IIB.

The aim of this study was to evaluate treatment results for Hodgkin lymphoma (HL) patients younger than 60 yr in stage IIB, treated according to the Swedish National Care Programme. The intention was also to identify specific subgroups depending on the number of negative prognostic factors the patients have, in order to optimise and differentiate future treatment. In total, 99 patients with HL stage IIB, diagnosed between 1985 and 1994, have been analysed. There were 47 men and 52 women and the median age was 33 yr (range 17-59). Eighty-six patients presented with supradiaphragmatic disease and 13 with infradiaphragmatic. The HL specific and overall 10-yr survival was 73 and 65%, respectively. The HL-specific survival for patients in pathological stage IIB tended to be better, although not statistically significant than for clinical stage IIB, despite less chemotherapy (P = 0.1). The patients in stage IIB who were selected for laparotomy were, however, younger and with fewer negative prognostic factors. The only significant negative prognostic factor was bulky disease (P = 0.001). The following factors also tended to have a negative influence on the prognosis although not statistically significant: the International Prognostic Score, the number of involved lymph node stations, extranodal involvement and leucocyte count > 15 x 10(9)/L. In conclusion, we suggest that bulky disease should be taken into account when treating patients with stage IIB HL.

A population-based study of the outcome for patients with first relapse of Hodgkin's lymphoma.

BACKGROUND: Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkin's lymphoma (HL). PATIENTS AND METHODS: In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995. RESULTS: Fifty-eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved-field RT, and four after a short course of CT followed by extended-field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5-yr Hodgkin-specific survival (HLS) was 85%, overall survival (OS) 73% and event-free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6-8 cycles) of CT the 5-yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis. CONCLUSIONS: Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

Early and late invasive pneumococcal infection following stem cell transplantation: a European Bone Marrow Transplantation survey.

Streptococcus pneumoniae (S. pneumoniae) may cause severe and lethal infections months and years following stem cell transplantation (SCT). In a prospective survey over a 3.5-year period, we assessed the incidence, risk factors and outcome for invasive pneumococcal infection (IPI) following SCT. Fifty-one episodes of IPI were reported: 43 episodes after bone marrow transplantation (BMT) and 8 after peripheral blood stem cell transplantation (PBSCT); 35 after allogeneic SCT and 16 after autologous SCT. Seven IPI episodes, all bacteraemias, were defined as early, occurring 1-35 d (median 3 d) post transplantation. Forty-four episodes were defined as late (> or = 100 d post SCT), occurring 4 months to 10 years (median 17 months) post transplantation. The incidences of early and late IPI were 2.03/1000 and 8.63/1000 transplantations respectively (P = 0.001). A higher incidence of late IPI was observed after BMT than after PBSCT (10.99 versus 3.23/1000; P < 0.01) and after allogeneic versus autologous SCT (12.20 versus 4.60/1000; P < 0.01). There was a higher estimated incidence of IPI in allogeneic patients with than in those without graft-versus-host disease (GVHD) (18.85 versus 8.25/1000; P = 0.015). The mortality rate was 20%, including 2/7 of early and 8/44 of late IPI. S. pneumoniae is a rare but important complication during the aplastic phase after SCT. In conclusion, S. pneumoniae is a significant cause of morbidity late post-transplantation, especially in allogeneic patients, and particularly those with GVHD. The high IPI mortality rate, both early and late post-transplantation, requires preventive approaches, mainly effective immunization.