G. Vaughan Hudson

Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial

High-dose chemotherapy and radiotherapy with autologous bone-marrow transplantation (ABMT) are increasingly used for the treatment of relapsed and resistant Hodgkins disease, although there has been no randomised trial of this treatment. The British National Lymphoma Investigation therefore undertook a randomised comparison of high-dose chemotherapy (BEAM = carmustine, etoposide, cytarabine, and melphalan) plus ABMT with the same drugs at lower doses not requiring bone-marrow rescue (mini-BEAM) in patients with active Hodgkins disease, for whom conventional therapy had failed. 20 patients were assigned treatment with BEAM plus ABMT and 20 mini-BEAM. All have been followed up for at least 12 months (median 34 months). 5 BEAM recipients have died (2 from causes related to ABMT and 3 from disease progression) compared with 9 mini-BEAM recipients (all disease progression). This difference was not significant (p = 0.318). However, both event-free survival and progression-free survival showed significant differences in favour of BEAM plus ABMT (p = 0.025 and p = 0.005, respectively). Recruitment to the trial became increasingly difficult because patients refused randomisation and requested ABMT. It was therefore closed early (40 patients rather than 66 intended). Nevertheless, we found a dose-response effect in these patients with relapsed and resistant Hodgkins disease. High doses facilitated by ABMT can lead to better disease-free survival.

Risk of Second Malignancy After Hodgkin’s Disease in a Collaborative British Cohort: The Relation to Age at Treatment

PURPOSE To assess long-term site-specific risks of second malignancy after Hodgkins disease in relation to age at treatment and other factors. PATIENTS AND METHODS A cohort of 5,519 British patients with Hodgkins disease treated during 1963 through 1993 was assembled and followed-up for second malignancy and mortality. Follow-up was 97% complete. RESULTS Three hundred twenty-two second malignancies occurred. Relative risks of gastrointestinal, lung, breast, and bone and soft tissue cancers, and of leukemia, increased significantly with younger age at first treatment. Absolute excess risks and cumulative risks of solid cancers and leukemia, however, were greater at older ages than at younger ages. Gastrointestinal cancer risk was greatest after mixed-modality treatment (relative risk [RR] = 3.3; 95% confidence interval [CI], 2.1 to 4.8); lung cancer risks were significantly increased after chemotherapy (RR = 3. 3; 95% CI, 2.4 to 4.7), mixed-modality treatment (RR = 4.3; 95% CI, 2.9 to 6.2), and radiotherapy (RR = 2.9; 95% CI, 1.9 to 4.1); breast cancer risk was increased only after radiotherapy without chemotherapy (RR = 2.5; 95% CI, 1.4 to 4.0); and leukemia risk was significantly increased after chemotherapy (RR = 31.6; 95% CI, 19.7 to 47.6) and mixed-modality treatment (RR = 38.1; 95% CI, 24.6 to 55. 9). These risks were generally greater after treatment at younger ages: for patients treated at ages younger than 25 years, there were RRs of 18.7 (95% CI, 5.8 to 43.5) for gastrointestinal cancer after mixed-modality treatment, 14.4 (95% CI, 5.7 to 29.3) for breast cancer after radiotherapy, and 85.2 (95% CI, 45.3 to 145.7) for leukemia after chemotherapy (with or without radiotherapy). CONCLUSION Age at treatment has a major effect on risk of second malignancy after Hodgkins disease. Although absolute excess risks are greater for older patients, RRs of several important malignancies are much greater for patients who are treated when young. The increased risk of gastrointestinal cancers may relate particularly to mixed-modality treatment, and that of lung cancer to chemotherapy as well as radiotherapy; there are also well-known increased risks of breast cancer from radiotherapy and leukemia from chemotherapy. The roles of specific chemotherapeutic agents in the etiology of solid cancers after Hodgkins disease require detailed investigation.

Clinical stage 1 non-Hodgkin's lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy.

A retrospective analysis was performed of 451 adult patients with clinical stage 1/1E non-Hodgkins lymphoma treated initially with radiotherapy alone. Histopathologically 208 patients had low-grade disease and 243 patients high-grade disease. The complete remission (CR) rate was higher in patients with low-grade disease (98%) than in those with high-grade disease (84%) (P < 0.0001). The relapse rate was similar in both histological categories, and relapse usually occurred within 5 years. The resulting overall actuarial percentage of patients achieving CR and remaining disease free (at 10 years) was 47% in patients with low-grade disease and 45% for those with high-grade disease. Salvage therapy was frequently successful in younger patients, and the overall cause-specific survival at 10 years was 71% for low-grade disease and 67% for high-grade disease. In those patients under 60 years of age at diagnosis, the overall cause-specific survival at 10 years was 84% and 80% for those with low-grade and high-grade disease respectively. These long-term results in young patients with clinical stage 1 disease are encouraging, and it will be difficult to demonstrate improved survival with initial chemotherapy either with or without radiotherapy, until new prognostic factors are found to identify poor-risk patients.

Lung Cancer After Hodgkin’s Disease: A Nested Case-Control Study of the Relation to Treatment

PURPOSE To investigate the causes of the raised risk of lung cancer in patients who have had Hodgkins disease, and in particular the relationship to treatment. PATIENTS AND METHODS A nested case-control study was conducted within a cohort of 5,519 patients with Hodgkins disease treated in Britain during 1963 through 1993. For 88 cases of lung cancer and 176 matched control subjects, information on treatment and other risk factors was extracted from hospital case-notes, and odds ratios for lung cancer in relation to these factors were calculated. RESULTS Risk of lung cancer was borderline significantly greater in patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy than those who did not receive this treatment (relative risk [RR] = 1.66; 95% confidence interval [CI], 0.99 to 2.82), and increased with number of cycles of MOPP (P =.07). Exclusion of lung cancers for which histologic confirmation was not available strengthened these associations (RR = 2.41; 95% CI, 1.33 to 4.51; P =.004 for any MOPP and P =.007 for trend with number of cycles of MOPP). Risks were not raised, however, after chlorambucil, vinblastine, procarbazine, and prednisone treatment. There was evidence that the raised risk of lung cancer occurring in relation to radiotherapy was restricted to histologies other than adenocarcinoma. CONCLUSION The results suggest that MOPP chemotherapy may lead to elevated risk of lung cancer, at least in certain subgroups of patients. The role of chemotherapy in the etiology of lung cancer after Hodgkins disease deserves further investigation.

Primary gastrointestinal non-Hodgkin's lymphoma: a review of 175 British National Lymphoma Investigation cases.

A retrospective analysis was performed upon 175 patients with Non-Hodgkins Lymphoma involving the gastrointestinal tract and entered into BNLI trials and studies between 1974-1988. Malignant histiocytosis of the intestine (MHI), which was present in 16 patients, was associated with a survival of less than 25% at 18 months, and probably accounted for the poor survival of patients with jejunal involvement. Histopathological evidence of tumour origin from mucosa-associated lymphoid tissue (MALT) was found in 50% of patients with gastric involvement and in 27% of those with intestinal involvement. The overall survival of the series as a whole was 44% at 10 years. Multivariate analysis identified evidence of tumour origin from MALT as the only factor to attain prognostic significance in patients with gastric involvement, and clinical stage and the presence of MHI as the only factors to attain prognostic significance in patients with intestinal involvement. It is suggested that there is a need for a large multicentre prospective study of GIT lymphoma.

Non-Hodgkin's lymphoma of the testis

Primary non-Hodgkins lymphoma of the testis is rare. From 1976 to 1989 32 patients have been registered with the British National Lymphoma Investigation and two with the Institute of Urology. All 34 patients had disease of high grade histology (BNLI) although in four patients there were some areas with features similar to those described in lymphomas of Mucosal Associated Lymphoid Tissue (MALT). Twenty-three of 34 (67.5%) patients had early stage disease (I/II); 17/34 (50%) achieved complete remission from their initial treatment, and the relapse-free survival of these patients was 66% at 5 years. The disease-free survival for the 34 patients as a whole was 33% and their overall survival 39% at 5 years. The life expectancy for those presenting with advanced (stage III/IV) disease was very poor (median survival 9 months) with a low complete remission rate from chemotherapy. The salvage rate from recurrent disease (17%) was poor. Bilateral testicular involvement (18%) and a high rate of central nervous system disease (21%) occurred in the series, and two patients were HIV positive. Stage at presentation was the most important prognostic factor.

The Significance of MALT Histology in Thyroid Lymphoma: A Review of Patients from the BNLI and Royal Marsden Hospital

Data from a series of 45 patients with Stage I and II non-Hodgkins lymphoma (NHL) of the thyroid gland were analysed retrospectively to determine the incidence and prognostic significance of histopathological features of tumour origin from mucosa associated lymphoid tissue (MALT). The overall 5- and 10-year cause specific survival from NHL for the series was 79%. Evidence of tumour origin from MALT was the only significant prognostic factor for overall survival identified by multivariate analysis of the series (P < 0.01). A total of 31 (69%) tumours showed such evidence, the cause specific patient survival from NHL at 5 and 10 years being 90% compared with only 55% at 5 years for the 14 patients without such evidence. For patients given initial treatment with radiotherapy alone, those with evidence of tumour origin from MALT had a relatively low relapse rate and a relatively high success rate from salvage therapy, compared with a relatively high relapse rate and negligible success from salvage therapy in those without evidence of such tumour origin.

Risk of second primary cancer after Hodgkin's disease in patients in the British National Lymphoma Investigation: relationships to host factors, histology and stage of Hodgkin's disease, and splenectomy.

The risks of second primary cancer were analysed in 2846 patients with Hodgkins disease treated within the British National Lymphoma Investigation during 1970-87. The relative risk (RR) of leukaemia was significantly greater in women (RR = 30.1; 95% confidence limits (CL) 13.0-59.5) than in men (RR = 10.9; 95% CL 4.7-21.5), and showed a significant trend of greater risk with younger age at first treatment (P < 0.001). The relative risk of solid cancers was similar between the sexes, but again significantly greater at young than at older ages of first treatment (P < 0.01). Non-Hodgkins lymphoma relative risks, although not related to sex or age, were significantly related to histology of the original Hodgkins disease, and were greatest after lymphocyte predominant Hodgkins disease (RR = 55.6; 95% CL 18.0-129.7). The relative risk of second cancers did not vary significantly according to whether or not splenectomy had been performed. Leukaemia risk was non-significantly greater after splenectomy than with no splenectomy, which accorded with previous evidence of a modest increased risk associated with this operation. If the greater relative risk of solid second cancers after treatment at young than at older ages persists with longer follow-up, the incidence rates of these second primaries in patients treated young for Hodgkins disease will become very substantial as they age. This emphasises the need to maintain long-term follow-up surveillance of young Hodgkins disease patients apparently cured of their disease, and to continue to develop new less carcinogenic treatment regimens.

Leukaemia complicating treatment for Hodgkin's disease: the experience of the British National Lymphoma Investigation.

OBJECTIVE--To determine the incidence of and risk factors for the development of secondary acute leukaemia and myelodysplasia in patients treated in British National Lymphoma Investigations studies of Hodgkins disease since 1970. PATIENTS--2676 Patients entered into Hodgkins disease studies between February 1970 and November 1986. Data accrued up to November 1988 were analysed, ensuring a minimum follow up period of two years. DESIGN--Retrospective analysis of multicentre trial data by case-control and life table methods. RESULTS--17 Cases of secondary leukaemia were recorded in this group of 2676 patients, giving an overall risk at 15 years of 1.7%. The risks of leukaemia after chemotherapy alone and chemotherapy with radiotherapy were not significantly different. The risk of leukaemia increased sharply with the amount of treatment given as measured by the number of attempts at treatment. The 15 year risks of leukaemia were 0.2%, 2.3%, and 8.1% for patients receiving one, two, or three or more attempts at treatment. The highest risk, 22.8% at 15 years, was observed in patients treated with lomustine (CCNU), and a case-control study suggested that this was an independent risk factor. The risk of secondary leukaemia was largely related to the overall quantity of treatment, although exposure to lomustine seemed to be an important risk factor. Treatment with both drugs and radiation was not more leukaemogenic than treatment with drugs alone. The greatest risk of secondary leukaemia was seen in multiply treated patients who were unlikely to be cured of Hodgkins disease. CONCLUSIONS--Avoidance of secondary leukaemia should be a minor factor in the choice of treatment for Hodgkins disease.

Long-term survival in Hodgkin's disease patients : a comparison of relative survival in patients in trials and those recorded in population-based cancer registries

The prognosis of Hodgkins disease (HD) has improved during the last 30 years. This study was planned to analyse long-term survival of LID patients and to compare survival rates estimated from clinical trials and population-based data. Individual data were analysed on 2,755 adult HD patients entering randomised clinical trials of the British National Lymphoma Investigation BN LI) between 1970 and 1987, and 5,064 patients with HD incident 1978-1984 recorded in the UK population-based cancer registries participating in the EUROCARE study. Relative survival of Hodgkins disease patients allowing for mortality expected from general population rates was analysed by a proportional hazards regression model including covariates. Although relative mortality decreased with longer follow-up, it was still significantly positive at 9-10 years after diagnosis in both the clinical trials and the population-based data sets. Relative mortality was worse for late stage than for early stage patients even at 10-15 years after first treatment (BNLI data). Whereas 10-year relative survival was identical in trials and population-based patients at ages under 45 years (> 69%), it was much higher in BNLI older patients than in the population-based patients. In the older age group (65-74 years) the BNLI patients had 39% relative survival whilst for the population-based patients it was only 27%, Generalisation of clinical trials results to the general population must be done with caution, especially for older patients.