Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma.

There is no consensus on the optimal chemotherapy regimen for Hodgkin's lymphoma patients > or = 60 years. We present our institution's results of 5 years, using CHOP-21 as standard for this patient group. Twenty-nine patients with a median age of 71 years (range, 60 - 91) were included in this cohort. Fifty-five percent had known co-morbidities. Stage I/IIA patients (38%) were treated with 2 - 4 cycles of CHOP followed by radiotherapy. Stage IIB - IV patients (62%) received 6 - 8 cycles of CHOP and for the majority (13/18 pts) no radiotherapy. Two treatment-related deaths occurred. Febrile neutropenia was the most common toxicity (31%). The complete response rate after CHOP +/- radiotherapy was 93%. With a median follow-up of 41 months, five patients have relapsed and four have died from Hodgkin's lymphoma. So far, no relapses have occurred after 2 years from the end of therapy. Overall survival and progression-free survival at 3 years were 79% and 76%, respectively. We conclude that CHOP-21 is a well-tolerated and effective treatment for elderly patients with Hodgkin's lymphoma.

Long-term risk of second malignancy after treatment of Hodgkin's disease: the influence of treatment, age and follow-up time.

BACKGROUND: To quantify the long-term risk of second cancers (SCs) up to 30 years after primary treatment for Hodgkin's disease (HD) Material and methods In the period 1968 to 1985, an unselected population of 1024 patients started treatment for HD at the Norwegian Radium Hospital (NRH) and were followed for SC from 1969 through 1998 by The Norwegian Cancer Registry. The median age at diagnosis of HD was 40 years, and the median time at follow-up was 14 years. RESULTS: Of 197 SCs, 14 were acute non-lymphocytic leukemia (ANLL), 31 non-Hodgkin's lymphoma (NHL) and 152 solid cancers. The standardized incidence ratio (SIR) was significantly increased for SCs as a group, and for the subgroups ANLL, NHL, lung cancer, breast cancer, stomach cancer and melanoma. ANLL was related to heavy treatment with chemotherapy (CT) and combined CT and radiotherapy (RT), NHL was not treatment related, and solid tumors were related to radiotherapy only or combined RT and CT. The SIR of ANLL and NHL reached a peak between 5 and 10 years after treatment. Solid and non-solid tumors increased with young age at diagnosis of HD and solid tumors increased with follow-up time up to 28 years CONCLUSION: In a long-term follow-up study of HD patients of all ages, the SIR of solid tumors was high in patients treated at young age and decreased with increasing age. Most solid tumors had started within or at the edge of the irradiated field, and SIR of solid tumors increased even 20-30 years after diagnosis.

Central nervous system involvement following diagnosis of non-Hodgkin's lymphoma: a risk model.

BACKGROUND: To determine the incidence and risk factors for central nervous system (CNS) relapse in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patient records were registered prospectively in successive patients with NHL admitted to the Norwegian Radium Hospital from 1980 to 1996. A total of 2514 patients had no CNS involvement at diagnosis and were treated according to standard protocols. The incidence and risk factors for CNS progression or relapse were examined retrospectively. RESULTS: In low-grade (L)-NHL, the risk of CNS involvement was low (2.8%). In high-grade (H)-NHL, lymphoblastic and Burkitt's NHL patients had a high risk of CNS recurrence (24.4%) at 5 years, and prophylaxis seemed to reduce this risk. For the other patients with H-NHL, the proportion with CNS involvement at 5 years was 5.2%. Multivariate analysis identified five independent risk factors, each present in >5% of patients: elevated serum lactate dehydrogenase, serum albumin <35 g/l, <60 years of age, retroperitoneal lymph node involvement and involvement of more than one extranodal site. If four or five of these risk factors were present, the risk of CNS recurrence was in excess of 25% at 5 years. CONCLUSIONS: The risk of CNS involvement in this study is comparable with the results from other large series. CNS prophylaxis is not recommended in any subgroup of L-NHL. The risk of CNS involvement among patients with either Burkitt's or lymphoblastic lymphomas is considerable and these patients should therefore receive intensive chemotherapy including systemic and intrathecal methotrexate. Patients with other types of H-NHL should receive adequate CNS prophylaxis if at least four of the five risk factors identified are present.

Late medical complications and fatigue in Hodgkin's disease survivors.

PURPOSE: Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkin's disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkin's disease (HD) may explain the high level of fatigue among HDSs. PATIENTS AND METHODS: Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies. RESULTS: HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P <.05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P <.01). No associations were found between cardiac sequelae or hypothyroidism and fatigue. CONCLUSION: Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.

Prognostic factors in 140 adult patients with non-Hodgkin's lymphoma with systemic central nervous system (CNS) involvement. A single centre analysis.

We examined retrospectively the outcome of patients with non-Hodgkin's lymphoma (NHL) with systemic involvement of the central nervous system (CNS) registered at The Norwegian Radium Hospital (NRH) from 1980 to 1996, in order to evaluate our treatment strategy for these patients. 170 of 2561 patients (6.6%) had CNS involvement, 140 (5.5%) systemic CNS lymphoma (SCNSL) and 30 (1.2%) primary CNS lymphoma (PCNSL). Description of the patients, time of SCNSL diagnosis, symptoms at CNS diagnosis, treatment and survival were registered. The overall median survival for the 140 patients with SCNSL was 2.6 months (95% confidence interval (CI) 2.1-3.2), only 12 patients are alive in complete remission (CR). Patients with CNS involvement at diagnosis, relapse or progression during treatment for NHL had a median survival of 5.4 months (95% CI: 0.3-10.6), 3.8 months (95% CI: 0.0-9.1), and 1.8 months (95% CI: 1.0-2. 7), respectively (P=0.001). 5 of the 8 patients consolidated with high-dose therapy (HDT) are in CR. Paresis was the only symptom that predicted survival for SCNSL. Patients above 60 years of age with CNS involvement at progression or relapse and those with paresis at the time of CNS diagnosis have a dismal prognosis. For these patients supportive therapy only should be considered. For patients under 60 years of age with chemosensitive disease, the trend was toward better prospects, and they should be offered intensive chemo-radiotherapy including HDT with autologous stem cell support.

Stage I high-grade non-Hodgkin's lymphoma.

We report long-term survival and prognostic factors in 252 patients with stage I high-grade lymphoma. Median patient age was 64 years and 49% of patients had extranodal lymphoma. Premenopausal women had less risk of extranodal lymphoma than older women or males (p < 0.002). Disease specific 5 and 15 years' survival in patients < 64 years was 83% and 76%, respectively; compared to 54% and 46% in patients > 64 years of age. Age, non-centroblastic histology, B-symptoms, and increased serum lactate dehydrogenase (LDH) were independently negative prognostic factors (p < 0.01), while extranodal, testicular, or bulky ( > 6 cm) lymphoma presentation were of no prognostic significance. A radiation dose of 40 Gy in 2 Gy fractions to the primary site prevented in-field relapse in 159 of 173 irradiated patients (92%) and only three of 173 patients (1.7%) had local relapse in the absence of systemic dissemination.

Late medical sequelae after therapy for supradiaphragmatic Hodgkin's disease.

A total of 221 consecutive early stage Hodgkin's disease (HD) patients were given mantle field irradiation only or in combination with chemotherapy in 1971-1991. In 1994 these patients responded to a mailed self-report questionnaire covering items on late medical symptoms. Of 200 patients (91%) who reported that their thyroid function had been tested, 110 patients (55% of those tested) had thyroid hypofunction at follow-up in 1994. Ninety-five patients (86% of patients with biochemical hypothyreosis) had started hormonal substitution. In 1993 and 1994, 101 of these patients who had received mantle field irradiation in 1980-1988 were called in for interview, clinical examination and thyroid function tests. Eighteen patients (18%) had started hormonal substitution treatment earlier, but 58 (70%) of the other 83 patients were found to have biochemical hypothyreosis. Of the 221 patients who completed the questionnaire, 66 patients (30%) reported dyspnoea on exertion for more than 3 years after treatment, 8 patients (4%) reported a history of myocardial infarction, 6 patients (3%) reported pericardial disease and 25 patients (11%) heart valve disease. Increased expenses incurred for dental care were reported by 106 patients (48%), increasing to 55% when Waldeyer's ring had been irradiated. The consequences of late sequelae after mantle field irradiation for future treatment are discussed.

[Late complications after treatment of Hodgkin's disease]. / Senkomplikasjoner etter behandling for Hodgkins sykdom.

Treatment of Hodgkin's disease involves chemotherapy and radiation. Both modalities may cause cardiac, pulmonary and thyroid side-effects. In a cross-sectional study, we aimed to assess the occurrence and severity of such complications. From 1980 to 1989, 129 Norwegian patients (< 50 years old) had curative treatment for Hodgkin's disease 116 (90%) of them participated in the study (follow-up period 5-13 years). Methods included lung function tests, chest X-rays, bicycle exercise tests, echocardiography and thyroid function tests. Nearly 30% of the patients reported dyspnoea on exertion and had associated reductions in lung function. Evidence of fibrosis occurred in 68%, but was associated with reduced lung function in only 12%. Pathological left-sided heart valve regurgitations were detected in 24% of the patients, pericardial thickening in 15%, and coronary artery disease in 5%. Biochemical hypothyreosis was found in 67% of the patients. We conclude that cardiac, pulmonary and thyroid dysfunctions are frequent long-term side-effects after treatment for Hodgkin's disease. We recommend annual screening of thyroid function and echocardiographic examination in patients who have received standard mantle field radiotherapy without cardiac shielding. Lung function testing should be done in individuals who require further radiation, chemotherapy or thoracic surgery.

Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin's disease: an echocardiographic study.

OBJECTIVE: To assess by echocardiography the occurrence and degree of late cardiac sequelae after treatment for Hodgkin's disease by radiation and chemotherapy. PATIENTS AND METHODS: In Norway from 1980 to 1988, 129 patients < 50 years old with Hodgkin's disease had curative treatment with mediastinal radiation, with or without chemotherapy. 116 (90%) of these patients (mean (SD) age 37 (7) years, 67 males) were examined by echocardiography 5-13 years after treatment. 40 healthy individuals (mean (SD) age 40 (11), 20 males) were examined as controls. All those examined were in regular sinus rhythm. RESULTS: Grade > 1 (scale 0-3) aortic and/or mitral valvar regurgitation was found in 24% of the patients (15% aortic, 7% mitral, and 2% aortic+mitral), affecting 46% of the females v 16% of the males (P < 0.001). Female gender was a significant risk factor for aortic and mitral regurgitation (odds ratio 4.7, 95% confidence interval 2.0 to 11.2), whereas age, period of follow up, radiation dose, and chemotherapy were not. Thickened pericardium was diagnosed in 15% of the patients. No risk factors were identified. No cases of pericardial thickening or valvar regurgitation grade > 1 were recorded in the control group. Mean values for measured and calculated indices of systolic and diastolic function were within the normal range for patients and controls. The patients had reduced E/A ratio compared with the healthy controls (E/A 1.1 v 2.0, P < 0.001). CONCLUSIONS: Abnormal left sided valvar regurgitation was detected in one fourth of the patients, affecting the aortic valve in more than half of the cases. Females had an increased risk of valvar regurgitation. Echocardiographic screening after high-dose mediastinal radiation is recommended.

Cardiopulmonary sequelae after treatment for Hodgkin's disease: increased risk in females?

BACKGROUND: The treatment of Hodgkin's disease (HD) involves irradiation and chemotherapy. Both modalities may cause heart and lung injury. We aimed to assess 1) the occurrence of such injury, 2) the extent to which combined versus single-organ-affection resulted in disability, and 3) whether determinants for cardiopulmonary injury could be identified. PATIENTS AND METHODS: A national cohort (n = 116) of HD patients (mean age 37 +/- 7 (SD) years, 67 males) was examined by interview, echocardiography, bicycle exercise test and lung function tests, 5-13 years after mediastinal irradiation with or without chemotherapy. RESULTS: Cardiac, pulmonary or combined sequelae occurred, respectively, in 21%, 15% and 19% of the patients affecting 75% of the females versus 41% of the males (P < 0.001). Of the patients with combined sequelae, 27% were disabled versus 4% of the rest (P < 0.05). Combined sequelae was associated with dyspnoea (P < 0.001) and reduced maximal exercise heart rate (P < 0.05). Compared to males, females had an increased risk of heart valve regurgitation (46% versus 16%, P < 0.001), pericardial thickening (22% versus 10%, P = 0.07) and reduced gas transfer (41% versus 22%, P = 0.03). Female gender was a significant risk factor for cardiac and/or pulmonary sequelae (OR 6.1, 95% CI 2.4-15.7), whereas age, follow-up period, smoking habits, histology, bulky mediastinal disease, radiation dose and chemotherapy were not. Mean exercise work capacity and O2-saturation were within normal limits. CONCLUSIONS: Although cardiac and/or pulmonary sequelae were detected in more than half of the patients, only combined injury was associated with disability, dyspnoea and reduced performance. Females had an increased risk of cardiopulmonary sequelae, which could not be explained by treatment-related differences between the genders.

Clinical stage I and II Hodgkin's disease: long-term results of therapy without laparotomy. Experience at one institution.

BACKGROUND: We concluded a program in which we administered radiotherapy only to clinical stages I and II Hodgkin's disease patients at standard risk, with the addition of 4 cycles of combination chemotherapy before radiotherapy for high-risk patients. PATIENTS AND METHODS: From 1980 to 1991, 313 patients with clinical stages I or II Hodgkin's disease underwent treatment in our hospital. Fifty percent of the patients in groups previously identified as being at high risk for relapse received 4 cycles of combination chemotherapy before radiotherapy. The remaining half of the patients received radiotherapy only. RESULTS: Low- and high-risk patients aged 15-59 years had, respectively, complete remission (CR) rates of 97% and 94%, 5-year survivals of 95% and 91%, and 5-year freedom from relapse (FFR) rates of 78% and 89%. Older low- and high-risk groups had CR rates of 97% and 93%, 5-year survivals of 60% and 56% and 5-year FFR of 77% and 93%, respectively. CONCLUSION: Here we present our favorable results after treating standard-risk patients with clinical stages I and II Hodgkin's disease with radiotherapy only. With the addition of chemotherapy, the rate of relapse in the high-risk patients was reduced below that of the standard-risk patients. Overall survival was the same for the high- and standard-risk patients.

Prognostic variables and results of salvage treatment in Hodgkin's disease.

Treatment results and prognostic variables were studied in 549 adult patients with Hodgkin's disease after first-line and salvage treatment. After first-line treatment, 479 out of 549 patients (87%) achieved complete remission (CR). During a mean observation time of 74 months, 99 patients (21%) relapsed. Sixty-nine patients (70% of relapsed patients) achieved a second CR. Variables predicting poor response (< CR) and shortened survival after first-line treatment were advanced disease, B-symptoms and age >60 years. In relapsing patients, age >60 years, relapse within 12 months and non-CR after relapse treatment predicted a poor prognosis, and none of these patients were alive after 10 years. Localized disease at diagnosis and relapse, and relapse later than 24 months predicted a good prognosis with 10-year survival after relapse of 68% and 57%, respectively. Patients with a second relapse had 5-year survival of 28% and 10-year survival of 14%. Based on the prognostic variables at first-line treatment and at relapse, selection of patients to more intensive treatment is discussed.

A high-pressure liquid chromatographic method for measuring mitotane [1,1-(o,p'-Dichlorodiphenyl)-2,2-dichloroethane] and its metabolite 1,1-(o,p'-Dichlorodiphenyl)-2,2-dichloroethene in plasma.

The adrenolytic agent mitotane [o,p'-DDD or 1,1-(o,p'-dichlorodiphenyl)-2, 2-dichloroethane] has been employed in the nonsurgical treatment of patients with adrenal carcinoma for several decades. Its use is hampered by serious side effects, which may be limited by analytically guided dose modifications in the individual patient. Mitotane analyses have previously been undertaken by gas chromatography with electron capture detection. A sensitive high-pressure liquid chromatographic method for measuring mitotane in plasma is described. After protein precipitation with 1.5 vol of acetone, mitotane and its metabolite 1,1-(o,p'-dichlorodiphenyl)-2,2-dichloroethene (o,p'-DDE) are resolved by isocratic elution from a C18 reversed-phase support and quantified by ultraviolet detection at 230 nm. Recoveries of mitotane and o,p'-DDE after deproteinization were quantitative. Within-run and between-day coefficients of variation were < 4% over the entire therapeutic range. The limit of detection was 0.25 mumol/L and the standard curve was linear in the 1-100 mumol/L range. The method has been evaluated using samples obtained from an adolescent girl who had metastatic adrenocortical carcinoma. Data from this single patient may suggest that systemic absorption of mitotane is adequate, and toxicity possibly decreased, when mitotane is administered by the rectal route.

Lung function impairment in long-term survivors of Hodgkin's disease.

BACKGROUND: Treatment of Hodgkin's disease (HD) involves radiation and chemotherapy, modalities known to cause lung injury. PATIENTS AND METHODS: In Norway, between 1980 and 1988, 129 patients aged less than 50 years at the time of diagnosis, had curative treatment with thoracic radiation alone or combined-modality therapy for supradiaphragmatic HD. We have examined 116 (90%) of these patients by interview, chest X-ray and lung function tests, 5-13 years after treatment. RESULTS: Nearly 30% of the patients had dyspnoea on exertion and associated reductions in total lung capacity (TLC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and gas transfer (TLCO) (p < 0.05). Radiographic evidence of no, slight or moderate fibrosis occurred in 32%, 54% and 14% of the patients, respectively. Moderate fibrosis was associated with reductions in FVC, FEV1 and TLCO (p < 0.05). Radiation plus chemotherapy containing bleomycin-anthracyclines (median cumulative bleomycin dose 120 mg) was associated with decreases in FVC and TLCO (p < 0.05). In the multivariate analysis, chemotherapy with bleomycin-anthracyclines was the only significant predictor for lung function impairment. CONCLUSION: More than five years after therapy, respiratory symptoms and reduction in lung function were diagnosed in nearly one-third of otherwise healthy HD survivors.

A 10-year experience with splenectomy in patients with malignant non-Hodgkin's lymphoma at the Norwegian Radium Hospital.

BACKGROUND: Splenectomy is a major surgical intervention that has many implications for patients with malignant non-Hodgkin's lymphoma. As debated during the last few decades, the therapeutic benefit must outweigh the surgical risk and the loss of cellular immunity. A more liberal attitude toward splenectomy developed during the years 1980-1990 at the Norwegian Radium Hospital, as illustrated by the higher number of operations performed in the last 5 years (21 patients) compared to the first 5 years (14 patients). METHODS: A 10-year retrospective review of the effects and side effects of splenectomy in 35 patients with malignant non-Hodgkin's lymphoma was performed, based on information obtained from the patient files at the authors' institution. RESULTS: Clinical Stage IV disease was found in 29 patients (83%), and B symptoms in 15 patients (43%). At diagnosis, 26 patients (74%) had splenomegaly, and 8 patients (23%) had primary splenic lymphoma. The surgical mortality was 2.9%, and the morbidity was 37%. Infection was the most common complication, occurring in seven patients (20%). Pneumococcal vaccination had been performed in 13 patients, and the frequency of septicemia and pneumonia tended to be higher during follow-up in unvaccinated patients (not significant). Blood counts returned to normal during the first postoperative month in 18 of 25 patients (72%) who had cytopenia. After splenectomy, a durable remission was achieved in five patients (14%) who did not receive subsequent treatment. CONCLUSIONS: Splenectomy has the potential to relieve local symptoms, correct cytopenias, and modify the disease course in patients with malignant non-Hodgkin's lymphomas, even in advanced stages, at the cost of an acceptable operative risk.

Magnetic resonance imaging and 67gallium scan in mediastinal malignant lymphoma: a prospective pilot study.

BACKGROUND: A residual mediastinal mass is common after treatment for bulky mediastinal lymphoma and represents a difficult diagnostic problem. PATIENTS AND METHODS: 19 patients with bulky mediastinal masses due to malignant lymphoma had computed tomography (CT), magnetic resonance imaging (MRI) and 67Gallium scan (67Ga) before treatment, after four cycles of chemotherapy, and two, six and twelve months after end of treatment. RESULTS: MRI and 67Ga showed active tumor in all patients before treatment. Twelve months after treatment full consistency was found between the results of the two techniques. During treatment and the first six months after treatment, the two techniques were not in accord in some patients, partly due to later normalization of MRI compared with 67Ga. CONCLUSION: Both MRI and 67Ga are useful in assessing tumor activity in lymphoma mediastinal masses.

[Infrastructure for clinical research in a hospital]. / Infrastruktur for klinisk forskning i et sykehus.

Clinical research in hospitals involves many partners. In Norway, the doctors are allocated little time for clinical research. Furthermore, complicated laws and directives have to be followed. The authors describe the organisation of clinical research and a software collection, including CD-ROM. We conclude that clinical research in large hospitals demands both a strong organisation and extensive use of modern information technology. The problems can be solved at acceptable cost.

[Hodgkin's disease or lymphogranulomatosis. New views on prognosis, complicating conditions and complications after treatment]. / Hodgkins sykdom eller lymfogranulomatose. Nyere synspunkter på prognose, følgetilstander og komplikasjoner etter behandling.

Between the years 1968-85, 1,177 patients started treatment for Hodgkins disease at the Norwegian Radium Hospital. In this unselected material from Norway the age distribution was bimodal with the highest incidence between 20-40 years of age. Survival is dependent on age, stage and histology, and was better between the years 1980-85 as compared with the period 1974-79. During the last ten years, treatment has been decentralized in Norway, and all centres cooperate by using the same protocol for staging and treatment. The article summarizes the results of the treatment, and related complications.

[New cancer disease after treatment of Hodgkin's disease]. / Ny kreftsykdom etter behandling for Hodgkins sykdom.

The risk of a second cancer was assessed in 1,152 patients with Hodgkins disease who were treated at the Norwegian Radium Hospital from 1968-85. 68 patients developed a second cancer more than one year after the diagnosis of Hodgkins disease. These included nine acute non-lymphocytic leukemias, eight non-Hodgkins lymphomas and 51 solid tumours, including 11 lung cancers. The overall relative risk (observed/expected ratios) of developing a second cancer was 1.86. After 18 years the cumulative risk of developing a second cancer was 14.4% +/- 2.9%, of which 11.2% +/- 2.6% referred to solid tumours. The cumulative risk of leukemia appeared to reach a plateau level of 1.5% after 12 years while the risk of non-Hodgkins lymphomas and lung cancer continued to rise with time to 2.1% and 3.3% respectively after 18 years. The risk of developing leukemia increased after treatment with alkylating agents and Procarbazine. The risk of non-Hodgkins lymphoma was not related to any specific type of therapy. Excess lung cancer risk was noted in patients treated with radiotherapy, and the cancers appeared within the treated areas.