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.

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.

The diagnosis of Hodgkin's disease in surgically excised spleens.

A series of 44 spleens removed from patients with Hodgkin's disease before treatment has been reviewed. The difficulties encountered in detecting foci of Hodgkin's tissue and the histological features and characteristics of early invasion are described.

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.

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.

An assessment of the value of spleen scanning in the staging of Hodgkin's disease.

The value of non-invasive spleen scanning with 51Cr-chromate heat damaged red cells has been assessed in 68 patients with histologically proved Hodgkin's disease in whom pre-treatment laparotomy with splenectomy was performed. The scans were reported independently by two observers. Following this, the uptake pattern of the radioactive tracer and size of organ on the scan were compared with the post-operative weight and pathology of the spleen. From these results it is concluded that this method of spleen scanning is an unreliable technique in staging Hodgkin's disease.

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.

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.

Hodgkin's disease: the pendulum swings. Knox lecture, Royal College of Radiologists, 1977.

There has been a profound change in the attitude of the medical profession towards patients with Hodgkin's disease. Until recently the disease was regarded, quite incorrectly, as inevitably fatal. Nowadays it is frequently assumed that it is constantly curable, which also a totally erroneous view. However, there has been an enormous improvement in the management of patients with all stages of the disease, so much so that further improvements without the production of excessive complications are becoming increasingly difficult to achieve. The author reviews the background to the present situation including some of the studies organised by the British National Lymphoma Group, which may be producing results which could be of benefit for patients. Some measures are discussed which may offer hope of improving even further the situation for the patient, without increasing risks from treatment.

Diagnostic laparotomy in non-Hodgkin's lymphoma.

Twenty patients with non-Hodgkin's lymphoma (NHL) were investigated by diagnostic laparotomy. These patients were seen over a 3 1/2 year period during which a total of 78 patients with NHL were seen. Laparotomy was considered unsuitable in 58 patients, either because widespread disease was easily demonstrated by simpler means or because of their poor general medical condition. Laparotomy revealed more extensive disease in 14 patients. Although laparotomy is proving to be a worthwhile investigative procedure, it is less likely to be useful as a routine investigation than is the case with Hodgkin's disease. Widespread involvement of mesenteric lymph nodes is common and among the 10 patients with a poor histological grade of tumour, 2 with negative laparotomy findings developed disease in the abdomen within 3 months of operation.

Patterns of relapse following radiotherapy for Hodgkin's disease.

A study of the relationship between bulk disease and sites of relapse has been undertaken in 95 patients treated by radiotherapy for early stage Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. In a group of 80 pathologically staged patients the pattern of relapse in 39 patients confirms an association between recurrence and sites of bulk involvement in the mediastinum, neck and axilla. Bulk disease predisposes to recurrence by virtue of local failure inside the treatment volume as well as marginal recurrence. A small number of patients relapsed initially in sites that were irradiated prophylactically.

Factors affecting relapse following chemotherapy for Hodgkin's disease.

A study of the factors affecting relapse following combination chemotherapy has been undertaken in 64 previously untreated patients with Hodgkin's disease. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. Bulk disease was significantly more common in the treatment failure group, being present in 23 out of 37 patients who failed compared to eight out of 27 patients who remain relapse-free (P less than 0.025). Reduced drug dosage was associated with treatment failure in 19 out of 37 patients receiving suboptimal chemotherapy compared to only four of 27 patients in the relapse-free group (P less than 0.01). Patients over the age of 50 years were more likely to receive suboptimal drug dosages (P less than 0.05).

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.

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 response to treatment of nodular sclerosing Hodgkin's disease with extranodal involvement.

A study of the relationship between extranodal involvement and subsequent relapse has been undertaken in 32 patients with Stage IV nodular sclerosing Hodgkin's disease treated by chemotherapy. All patients were investigated and treated according to protocols of the British National Lymphoma Investigation. The most significant observation is that patients classified Stage IV by virtue of contiguous extranodal extension from bulky nodal lesions are inadequately treated by chemotherapy alone. Overall, 11 out of 12 (E) stage patients had residual or recurrent disease following quadruple chemotherapy. Four of these patients have since been rendered disease-free by radiotherapy.

The pathological findings following laparotomy in Hodgkin's disease.

The pathological findings in 50 patients with Hodgkin's disease following laparotomy for diagnostic purposes are described. Forty-four patients had laparotomy before treatment and within a few months of the original diagnosis, while 6 patients had delayed laparotomies. The Rye histological classification was applied to the original lymph node biopsy, the abdominal lymph node and Hodgkin's tissue in the spleen. The variation in appearance both of these tissues and of the liver biopsies is discussed.