Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial.

BACKGROUND: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma. METHODS: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed. FINDINGS: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5.9 [range 0-17.8] years and for observation 6.7 [0.5-18.9] years, p=0.84; median cause-specific survival 9 [0-17.8] years and 9.1 [0.67-18.9] years, respectively p=0.44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0.0001, 0.03, and 0.03, respectively) and cause-specific survival (p=0.002, 0.008, and 0.001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years). INTERPRETATION: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.

A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma.

Local radiotherapy (RT) alone was compared with radiotherapy plus continuous oral chlorambucil (RT+CHL) for the treatment of localised, low grade non-Hodgkins lymphoma (NHL) in a prospective randomised study of 148 patients. After a maximum of 18 years follow up there was no significant difference in overall survival or disease free survival between the two treatment groups. Age greater than 50 years and low serum albumin at diagnosis correlated with a poor prognosis in the series overall. Over one third of patients with localised, low grade NHL may be cured by RT alone and adjuvant chlorambucil as initial therapy confers no survival advantage.

British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease--long term results.

From 1979-1983, 299 patients with stage III or IV Hodgkin's disease (HD) were randomised to receive cyclical chemotherapy with MOPP (mustine, Oncovin, procarbazine, prednisone) or LOPP (Leukeran substituted for mustine). Two hundred and ninety patients were evaluable. There was no statistically significant difference between the complete remission (CR) rates (63% for MOPP, 57% for LOPP), percentage of patients remaining disease free at 5 years (38% for MOPP, 35% for LOPP) and overall survival at 5 years (65% for MOPP, 64% for LOPP). On multivariate analysis younger age, grade I histopathology, absence of systemic symptoms, and normal albumin level were favourable prognostic factors for survival. Acute toxicity in the form of nausea/vomiting, myelosuppression, and phlebitis were less with LOPP than MOPP. Deaths in both groups were usually due to disseminated Hodgkin's disease; there were no infective deaths in the absence of Hodgkin's disease. Second malignancies occurred in six patients treated with MOPP--three acute myeloid leukaemia (AML), one non-Hodgkin's lymphoma (NHL), two carcinomas (Ca); with LOPP, four second malignancies occurred (one AML, one NHL, two Ca). These long term results confirm that LOPP is as effective as MOPP, and less toxic, in the treatment of advanced Hodgkin's disease.

Relationship of histopathologic features to survival and relapse in nodular sclerosing Hodgkin's disease. A study of 1659 patients.

Nodular sclerosing (NS) Hodgkin's disease (HD) with extensive areas of lymphocyte depletion or with numerous anaplastic Hodgkin's cells, termed Grade II NS, is associated with a poor response to initial therapy, an increased relapse rate, and decreased survival when compared with other NS variants, termed Grade I NS. The histopathologic subdivision of NS HD into Grade I and Grade II is easy to perform and provides essential prognostic information that is independent of stage. Patients with Grade II NS HD may require more aggressive initial therapy if their survival is to be improved.

The prognostic influence of mediastinal bulk in pathological stage IIA Hodgkin's disease treated initially with radiotherapy.

The response to treatment and survival has been assessed in 61 patients with pathological Stage IIA Hodgkin's disease with mediastinal involvement who were treated initially by supradiaphragmatic radiotherapy alone. Although 57 (93%) obtained complete remission, 29 have relapsed giving a total of 33 (54%) treatment failures. The percentage of patients actuarially disease free at 5 years is 44% although overall survival is 90%. The "bulk" of the mediastinal disease was assessed on a plain chest X-ray by measurement of the widest diameter of the mass compared to thoracic diameters at various levels as well as by determination of the area of the mass. The ratio of the widest diameter of the mass to the widest internal thoracic diameter provided the greatest prognostic information. Patients with a ratio greater than 0.33 (30% of total) had an actuarial disease-free survival of 24% at 5 years compared to 54% in patients with smaller mediastinal masses (P less than 0.05). Mediastinal bulk was not correlated with histological grade. Patients with the largest mediastinal masses (ratio greater than 0.37) (10% of total) have a lesser survival, but in the remainder, measurement of the mediastinal mass did not predict survival, indicative of the excellent salvage rate with subsequent chemotherapy. The implication of these findings for the treatment of stage IIA Hodgkin's disease with mediastinal involvement is discussed.

Localized grade I non-Hodgkin's lymphoma: results of treatment with radiotherapy alone in 88 patients.

Eighty-eight patients entered into the British National Lymphoma Investigation with clinical stage I and II, grade I non-Hodgkin's lymphoma were treated initially with involved field radiotherapy alone. Eighty-one per cent presented with nodal disease. The duration of follow-up was 25-116 months, with a median of 54 months. Fifteen patients died of disease and the 5-year survival of the whole group was 83%. The complete response rate was dependent on the radiotherapy dose and was greater than 90% for doses of 3500 cGy and over. Most failures occurred at distant rather than adjacent sites, suggesting that extended field radiotherapy would not have affected the outcome. Second-line treatment induced complete remission in 66% of patients who relapsed. The prognosis was significantly worse in patients with intra-abdominal disease.

Magnetic resonance imaging: comparison of four pulse sequences in assessing primary bone tumours.

A prospective magnetic resonance imaging (MRI) study was carried out in 13 patients (19 examinations) with primary bone tumours to assess the relative value of each of four pulse sequences in showing the extent and nature of the lesion. The four pulse sequences used were a T1-weighted spin-echo (SE544/44), a T2-weighted spin echo (SE1500/80), a short TI inversion recovery (STIR) (IR500/100/44), and a partial saturation (PS) (PS500/22) with field echo data collection. For soft tissue disease the combination of PS and STIR gave better definition of the boundary of the tumour than the more conventional T1 and T2-weighted spin echo sequences. For the demonstration of bone cortex, periosteal change and calcification, T1 and T2-weighted spin echo sequences were better. However, for calcified tissues, plain radiographs were better than either MRI combination. On the assumption that plain films will be available in all cases, PS and STIR sequences could therefore be substituted for T1 and T2-weighted spin echo sequences allowing an increase in soft tissue detectability for lesions in both red and yellow marrow.

MR imaging of lymphomas: impact on therapy.

Seventy-six patients with either Hodgkin disease or non-Hodgkin lymphoma underwent magnetic resonance (MR) imaging as part of their evaluation. In this report the unique and common MR findings of these neoplasms are reviewed in each of the major anatomic sites. Further, the impact of these findings on therapy decisions and follow-up is emphasized.

The value of staging bone marrow trephine biopsy in Hodgkin's disease.

A retrospective study of pre-treatment bone marrow biopsies was undertaken to examine the value of bone marrow staging in Hodgkin's Disease. Bone marrow biopsy revealed infiltration in 40 out of 613 cases, (6.5%). These patients were not significantly different from stage 4 patients without marrow involvement with regard to age, sex, anaemia or survival. Peripheral blood lymphopenia and lymphocyte depleted histopathological type were more common in patients with marrow involvement. Bone marrow biopsy altered individual patient management in less than 1% of 613 patients and can no longer be recommended as part of the routine staging in Hodgkin's Disease.

Systemic disturbance in Hodgkin's disease and its relation to histopathology and prognosis (BNLI report No. 30).

Systemic disturbances in Hodgkin's disease at presentation are not only manifested by 'B' symptoms (weight loss, fever, and night sweats), but are also mirrored in the peripheral blood as raised sedimentation rate, low haemoglobin, low albumin, and abnormal lymphocyte counts. Such systemic disturbance is more common than consideration of classical 'B' symptoms alone would suggest. In a series of 840 patients, 88% had some form of systemic disturbance on these criteria. Survival after treatment was found to be closely and inversely related to the degree of systemic disturbance present before treatment. Patients with no evidence of such disturbance had an almost 100% survival at 10 years. In the absence of 'B' symptoms the sedimentation rate was the most useful prognostic blood parameter, enabling about one third of the patients to be identified as having an excellent chance of survival, and identifying a further 12% as having a survival almost identical to that of patients with 'B' symptoms. The latter patients were those with a sedimentation rate of 60 mm/h or greater, and it is suggested that the term 'Systemic Symptoms' should be broadened to include a sedimentation rate of this magnitude. The degree of malignancy of the tumour, as reflected by histopathology, plays a dominant role in determining the amount of systemic disturbance in the host. However, the amount of disturbance varies amongst individual patients with the same histopathological subtype, reflecting either differences in the malignancy of the tumour within such subtypes, or differences in the constitution of the host.

Incidence and clinical importance of bone marrow eosinophilia in Hodgkin's disease (BNLI Report No 29). British National Lymphoma Investigation.

A retrospective study of 136 bone marrow aspirates was undertaken before treatment to evaluate the importance of bone marrow eosinophilia in Hodgkin's disease. This occurred in 28 patients (21%) but did not correlate with age, sex, B symptoms, histopathological type or peripheral blood count. It also had no effect on survival. Bone marrow eosinophilia, therefore, seems to represent a common but non-specific reaction to Hodgkin's disease.

Selective peripheral blood eosinophilia associated with survival advantage in Hodgkin's disease (BNLI Report No 31). British National Lymphoma Investigation.

A peripheral blood eosinophilia was found at presentation in 193 of 1260 (15%) patients with Hodgkin's disease who had been entered into clinical studies by the British National Lymphoma Investigation (BNLI). Eosinophilia as a component of a general leucocytosis conferred no survival advantage. Eosinophilia without a general leucocytosis was present in 95 patients, and this selective eosinophilia was associated with a clear survival advantage. The association of selective eosinophilia and improved survival was limited to patients with mixed cellularity and grade I nodular sclerosis histology. Selective eosinophilia was found to be a good prognostic indicator both in local and generalised disease. Its survival advantage seemed to lie in the response to second line treatment following relapse.

Hodgkin's disease in childhood: the British National Lymphoma Investigation experience (BNLI Report No 27).

The experience of the British National Lymphoma Investigation in the treatment of 68 children with Hodgkin's disease is reported over a 14 year period from 1970. The presenting histology was reviewed by a single histopathologist; 87% of the cases were classified as nodular sclerosis (NS) and further subdivided into NSI (53%) and NSII (35%). Primary treatment consisted of local (involved field) or prophylactic (extended field) irradiation, combination chemotherapy alone or low dose irradiation and chemotherapy. An overall 5 year survival of 87% was achieved and a 5 year relapse-free survival of 64%. Eight deaths were reported during the study, all of which occurred in children who presented with NSII histology. Each child was in relapse and undergoing chemotherapy at the time of death. This histological subtype was also associated with both a lower complete remission rate and a reduced response to second line chemotherapy.

Very high dose chemotherapy with autologous bone marrow rescue in adult patients with resistant relapsed lymphoma.

Seventeen patients with advanced lymphoma were treated with high-dose chemotherapy with autologous bone marrow rescue. In 11 patients with non-Hodgkin's lymphoma (NHL) there were 2 complete remissions (CRs) and 2 partial remissions (PRs), and in 6 patients with Hodgkin's disease there were 5 CRs. Three patients remain well in unmaintained remission (days 874, 446 and 351), and a further 2 are alive and still receiving treatment (days 650 and 558). This type of therapy appears useful and should now be considered earlier in the course of the disease.

Review of British National Lymphoma Investigation studies of Hodgkin's disease and development of prognostic index.

A review of data from the British National Lymphoma Investigation (BNLI) studies of Hodgkin's disease (HD) done over the past 14 years shows (i) that systemic chemotherapy is appropriate for all clinical stages except I and IIA, and that MOPP (mustine, vincristine, procarbazine, and prednisone) courses are substantially more effective than MOP (the same without prednisone) but no better than the less toxic LOPP combinations (where chlorambucil replaces mustine); (ii) that local involved-field irradiation in stages I and IIA HD is as effective as wide-field in terms of both overall and recurrence-free survival; and (iii) that, histologically, nodular sclerosing HD can be divided into grades 1 and 2, the latter containing areas of lymphocyte depletion or numerous pleomorphic Hodgkin's cells. A multivariate analysis of factors influencing prognosis in clinical stages I and IIA disease shows that laparotomy has no significant effect but that age, sex, erythrocyte sedimentation (ESR), the presence or absence of mediastinal involvement and, especially, pathological grade are the most important factors influencing overall survival, while ESR, pathological grade, and stage of disease (I or II) correlate with recurrence-free time. A prognostic "survival" index was developed; an index of greater than 7.5 indicated a poor prognosis and that chemotherapy was perhaps more appropriate than local radiation. Laparotomy is no longer justified as a routine procedure in staging HD, although it may still be useful in special circumstances and in some research investigations.

Differences in the effect of mediastinal radiotherapy on lung function and the ventilatory response to exercise.

To examine the effect of lung inflammation on lung volumes and carbon monoxide transfer and their relationship to the ventilatory and gas exchange responses to exercise, a prospective study was performed in patients having Hodgkin's disease, with no evidence of intrathoracic involvement, who received prophylactic mantle-field radiotherapy to the chest. From 6 weeks to 6 months from the start of therapy, vital capacity (FVC) was on average 10.4% lower than during the baseline period and the total transfer of carbon monoxide (TLCO) was 10.5% lower. Minute ventilation (VE) at any given work load during an incremental exercise test was on average 10.5% higher than baseline. The stimulation of ventilation after radiotherapy was present at all work rates, but greater at high work rates. A number of other changes in the ventilatory and gas exchange responses to exercise were also seen. Most of these lay outside the range of variability observed in a group of normal subjects tested concurrently with the patients. There was a poor, but statistically significant, positive correlation between reduction in FVC and increase in VE after radiotherapy and between reduction in carbon monoxide transfer and increase in VE. A significant correlation between reduction in FVC and change in respiratory rate was also seen after radiotherapy, together with a significant inverse correlation between increase in respiratory rate and fall in tidal volume. The ratio of VE to oxygen consumption, the ventilatory equivalent for oxygen, was calculated at each work rate. There was a negative correlation between the mean increase in this parameter, averaged over all work rates, and the reduction in FVC and TLCO, i.e. the greatest stimulation of breathing relative to metabolic demand occurred in those patients with the least change in lung volume.(ABSTRACT TRUNCATED AT 250 WORDS)

Localised grade 2 non-Hodgkin's lymphoma: results of treatment with radiotherapy (BNLI Report No. 24).

This report reviews 85 patients entered into the British National Lymphoma Investigation with localised (clinical Stage 1 and 2) Grade 2 non-Hodgkin's lymphoma, who were treated initially with radiotherapy alone. Almost half of all patients presented with extranodal disease. The duration of follow-up was 20-106 months. There were 33 deaths due to non-Hodgkin's lymphoma. The complete local response rate was dependent on the radiotherapy dose and reached 100% for doses of 4500 cGy or more. Most first failures occurred at a distant nodal site or were due to the development of generalised disease. There was a significant difference in actuarial survival between Stage 1 and Stage 2 patients (P less than 0.005). The 5-year survivals were 78% and 40%, respectively. The site of presenting disease was also important. Stage 1 patients with nodal or ear, nose and throat (ENT) disease had an excellent 5-year survival of 84%, but Stage 2 patients with nodal or ENT disease had a 5-year survival of only 46%. As many of these Stage 2 patients rapidly developed disseminated disease, their survival might have been improved by treatment with chemotherapy before radiotherapy.

The presentation haemoglobin level in 1103 patients with Hodgkin's disease (BNLI report no. 21).

The presentation haemoglobin level was measured in 1103 patients with Hodgkin's disease. A reduced presentation haemoglobin level occurred with a higher relative frequency in patients with advanced disease, systemic (B) symptoms and aggressive histological subtypes. A reduced presentation haemoglobin was associated with a decreased survival.