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.

Impact of high-dose salvage therapy (BEAM) on overall survival in younger patients with advanced large-cell lymphomas entered into BNLI trials.

The survival of two cohorts of patients with stage III/IV large-cell lymphomas treated by CHOP has been compared. In the first cohort of 88 patients (1974-1982), high-dose therapy with autologous bone marrow transplantation (ABMT) was not available as salvage therapy and in the second cohort of 87 patients (1987-1992), this was the recommended salvage for patients with disease that was still chemosensitive to conventional-dose therapy. The actuarial overall survivals at five years were 40% and 44% in the first and second cohorts, respectively, indicating that the availability of ABMT had made little impact. Of the 62 patients in the second cohort who failed CHOP therapy, 8 died before second-line chemotherapy could be given, 1 refused more therapy, and 8 were considered unsuitable for further combination chemotherapy. Seven patients with localized disease remaining received local radiotherapy. Of the 38 patients given salvage therapy, 14 had chemoresistant disease. Only 9 patients received high-dose BEAM chemotherapy and ABMT, and 7 remain disease-free. ABMT was restricted to a highly select patient group, and as a result more widespread application of this strategy might result in only a modest further improvement.

The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group.

Mantle cell lymphoma (MCL) was first described as a distinct biological entity on the basis of its association with the t(11;14)(q13;q32) resulting in over-expression of the cyclin D1 gene. Recognition of the morphological, immunophenotypic and clinical characteristics of MCL has enabled the accurate diagnosis of this entity and appreciation of its poor prognosis. Most published series of patients with MCL have used anthracycline-containing regimens. In contrast the British National Lymphoma Investigation (BNLI) group have treated 65 patients with MCL with non-intensive 'low-grade lymphoma' therapy. The median overall survival of 57 months and progression-free survival of 24 months compares favourably with the more intensively treated series. Although the disease was generally more aggressive than other low-grade lymphomas, some patients were asymptomatic and had indolent disease. When compared to 1853 patients with non-MCL low-grade lymphomas entered on the BNLI database, patients were found on average to be older (P=0.02), to have more extranodal disease (P<0.00001), and a higher proportion to have a raised ESR (P=0.02) and a low serum albumin (P=0.002). Multivariate analysis of significant prognostic markers in all BNLI low-grade lymphomas failed to identify MCL as an independent prognostic factor.

Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study.

The Bcl-2 protein is capable of preventing apoptosis, and in vitro evidence suggests a role in drug resistance. It is expressed and the gene is rearranged in a proportion of cases of large-cell non-Hodgkin's lymphoma (NHL), but the clinical significance of these findings is controversial. The purpose of this study was to determine the influence of both Bcl-2 expression and major breakpoint region (MBR) bcl-2 rearrangement in a large cohort of prospectively accrued patients with intermediate-grade B-cell NHL treated in a standardized manner. All patients with Working Formulation F, G, or H NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in British National Lymphoma investigation studies between July 1974 and April 1992 were considered for this study if the appropriate paraffin blocks were available. Paraffin sections from the diagnostic specimen were analyzed for evidence of MBR rearrangement using a polymerase chain reaction-based method, and for Bcl-2 expression using immunohistochemistry. Failure to achieve complete remission (CR), relapse, death from NHL, and deaths from all causes were used as end points to measure CR rate, actuarial relapse rate, actuarial survival from NHL, and actuarial overall survival. One hundred sixty-one suitable patients were identified and tested for the bcl-2 MBR translocation, with 27 (17%) found to be positive; 153 of these patients were tested with immunocytochemistry, and 84 (55%) showed evidence of Bcl-2 expression. For patients who achieved CR from the initial treatment, the relapse rate was significantly higher in those with Bcl-2 expression than in those without. In addition, multivariate analysis identified Bcl-2 expression as the only factor significantly related to relapse rate in the subjects measured. The cause-specific survival for NHL in the series as a whole was significantly lower in patients with Bcl-2 expression than in those without. MBR status had no significant influence on any of the outcome measures, but the number of MBR-positive patients was relatively small, and larger studies are required. In conclusion, in Working Formulation F, G, and H NHL of B-cell type, expression of Bcl-2 protein predicted independently for relapse.

A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report.

A combination of cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) has been a standard therapy for histologically aggressive non-Hodgkin's lymphomas for over 20 years, but several newer regimens, referred to as second or third generation, have been reported to give improved results in single-centre studies. Positive evidence from randomised trials has been lacking, and the British National Lymphoma Investigation therefore commenced a randomised comparison of CHOP vs a third-generation regimen, PACEBOM, in November 1987. A total of 459 eligible patients were entered into the trial: 226 in the CHOP arm and 233 in the PACEBOM arm. Overall, there was no significant difference in outcome between the two arms of the trial. In patients with stage IV disease there was an apparent improvement in survival for those treated with PACEBOM, but considerable caution must be exercised with such subgroup analysis.

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-Hodgkin's 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.

Efficacy and toxicity of vinblastine, bleomycin, and methotrexate with involved-field radiotherapy in clinical stage IA and IIA Hodgkin's disease: a British National Lymphoma Investigation pilot study.

PURPOSE: To assess the efficacy and toxicity of vinblastine, bleomycin, and methotrexate (VBM) chemotherapy with involved-field radiotherapy in clinical stage IA and IIA Hodgkin's disease. PATIENTS AND METHODS: Thirty eligible patients with clinical stage IA or IIA Hodgkin's disease, at intermediate risk of relapse, were enrolled into a prospective multicenter pilot study. They received two cycles of VBM chemotherapy, followed by involved-field radiotherapy and then four further cycles of VBM. The median follow-up duration from the start of treatment is 30 months. RESULTS: All 26 patients with assessable disease showed an objective response after two cycles of VBM (nine complete responses, 17 partial responses). By the completion of treatment, 27 patients were in complete remission; two had stable residual masses, which have not progressed at 26 and 34 months of follow-up; and one patient who died of treatment-related sepsis was in complete remission at that time. Two relapses have occurred, 19 and 28 months after starting VBM. Cough and dyspnea developed in 14 of 30 patients, and were associated with impairment of pulmonary function tests. Three episodes of neutropenic sepsis were recorded. CONCLUSION: VBM with involved-field radiotherapy is an effective treatment for early Hodgkin's disease. However, the associated toxicity, both pulmonary and hematologic, is severe, making the regimen unsuitable for routine use.

Hybrid LOPP/EVA is not better than LOPP alternating with EVAP: a prematurely terminated British National Lymphoma Investigation randomized trial.

In a British National Lymphoma Investigation (BNLI) trial, patients with advanced Hodgkin's disease (stages IB, IIB, III, and IV) were randomized between initial treatment with a LOPP alternating with EVAP regimen and a LOPP/EVA hybrid regimen. The two regimens contained identical drug dosages and varied only in their scheduling. The complete remission (CR) rate in the hybrid regimen was significantly less than that in the alternating regimen, and the trial was terminated after approximately 18 months since there appeared to be no chance of the hybrid regimen ever proving superior to the alternating regimen. A total of 160 patients were entered into the trial before recruitment was terminated, 86 being randomized to the alternating regimen and 83 to the hybrid regimen. The CR rates for the alternating and hybrid arms were 65% and 40%, respectively (p < 0.002). The CR relapse-free survivals at 2 years in these two arms were 85% and 79%, respectively (p = 0.7); the overall disease-free survivals at 2 years were 57% and 32%; and the overall survivals at 2 years were 88% and 78% (p = 0.5). This trial emphasizes the impact of drug scheduling, which should be taken into account in the design of future hybrid regimens.

Late mortality in young BNLI patients cured of Hodgkin's disease.

A retrospective analysis was made of 1057 young patients (aged 15-29) with Hodgkin's disease (HD) who were entered into British National Lymphoma Investigation (BNLI) trials and studies between 1970 and 1992, and who had attained complete remission and remained disease-free thereafter from either their first-line (n = 774) or second-line (n = 283) treatment. Overall survivals at 20 years for those remaining disease-free from first-line and second-line treatment were 93% and 84%, respectively, compared to a survival of approximately 98.5% in the general population. In young patients cured by modern first-line therapeutic techniques, long-term survival should in future be only a little below that expected in the general population, and the emphasis of future trials should be directed towards the improvement of the efficacy of first-line treatment.

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 Hodgkin's 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-Hodgkin's lymphoma relative risks, although not related to sex or age, were significantly related to histology of the original Hodgkin's disease, and were greatest after lymphocyte predominant Hodgkin's 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 Hodgkin's disease will become very substantial as they age. This emphasises the need to maintain long-term follow-up surveillance of young Hodgkin's disease patients apparently cured of their disease, and to continue to develop new less carcinogenic treatment regimens.

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-Hodgkin's 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.

Completeness of cancer registration in England and Wales: an assessment based on 2,145 patients with Hodgkin's disease independently registered by the British National Lymphoma Investigation.

Records of 2,145 cases of Hodgkin's disease in England and Wales treated by the British National Lymphoma Investigation during 1970-84 were sought in the national and regional cancer registers. One thousand eight hundred and eight-six (88%) were recorded in the national register, either as Hodgkin's disease (86%) or as other or unspecified lymphoma (2%) and 2 (0.1%) were recorded as other cancers. A further 69 (3%) cases were registered by regional cancer registries but had not reached the national register. Adjusting for the distribution of the study cases by region of incidence, we estimate completeness of registration of cases of Hodgkin's disease in the national register at 89.7%, and in the regional registers overall at 92.9%. Completeness did not vary appreciably by age or sex or calendar period. There was however, substantial variation in completeness between regional registries. Estimates were made for all regions except North Western; the lowest estimated completeness were under 90% in Wessex, and the Thames registry regions, and the greatest were 95% or more in Northern, Trent, East Anglia, Oxford, South Western, West Midlands and Mersey. Because these results are confined to one malignancy treated by a particular collaborative network of physicians (although a large and widespread one), and because the patients are restricted to those seen in hospitals, caution must be exercised in extrapolation of the findings to cancer registration generally, but other studies and sources of information lead to similar conclusions about completeness of cancer registration nationally and regionally.

LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial.

PURPOSE: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone (LOPP) with four cycles of LOPP that alternate with four cycles of etoposide, vinblastine, Adriamycin (doxorubicin; Familitalia Carlo Erba, Ltd, UK), and prednisone (EVAP) in patients with advanced Hodgkin's disease. PATIENTS AND METHODS: Between June 1983 and December 1989, 594 patients were entered onto the study. Of the 594, 295 patients were allocated to receive LOPP, and 299 were allocated to receive LOPP/EVAP. RESULTS: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NS]), and 65% and 75%, respectively, after the subsequent administration of radiotherapy to residual masses (P less than .01). The procedure associated mortality in the LOPP and LOPP/EVAP arms was 1% and 3%, respectively. The actuarial CR relapse-free survival was significantly greater in the LOPP/EVAP arm (P less than .001) as was the overall survival (P less than .05). The CR relapse-free rate, disease-free survival (DFS) rate, and overall survival rate at 5 years were 52%, 32%, and 66%, respectively, in the LOPP arm, compared with 72%, 47%, and 75% in the LOPP/EVAP arm, respectively. CONCLUSION: These results indicate that LOPP and EVAP is superior to LOPP alone as initial treatment for advanced Hodgkin's disease.

Failure of IMVP-16 as second-line treatment for relapsed or refractory high grade non-Hodgkin's lymphoma.

The British National Lymphoma Investigation (BNLI) has assessed the use of an IMVP-16 regimen (ifosfamide, methotrexate, VP-16) in 46 patients with high grade non-Hodgkin's lymphoma (NHL) who on first-line chemotherapy either failed to attain a complete remission or relapsed. Seventeen patients responded to IMVP-16 but only five (11 per cent) went into a complete remission (CR), 12 (26 per cent) had a partial remission (PR) and 29 (63 per cent) showed no response (NR). CR after IMVP-16 has been maintained in only one case (36 months). The results of this study imply that the use of this IMVP-16 protocol as second-line treatment for patients with recurrent high grade NHL is unsuccessful and alternative salvage regimens should be sought.

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.

Non-Hodgkin's lymphoma arising in patients treated for Hodgkin's disease in the BNLI: a 20-year experience. British National Lymphoma Investigation.

Twenty-two of 3033 patients with Hodgkin's disease (HD) randomised into the clinical trials of the BNLI have developed non-Hodgkin's lymphomas (NHLs) at periods up to 16 years after presentation (1 simultaneous and 1 composite), giving an incidence of 0.7%. The frequency of NHL varied from 3.8% in lymphocyte-predominant HD to 0.3% in nodular sclerosing HD. In this series, 16 patients developed high-grade NHL (12 B cell; 4 peripheral T cell) and 6 developed low-grade NHL (all B cell). The histological subtype of NHL did not appear to be related to initial histological subtype of HD or the treatment received. In histological subtypes other than lymphocyte predominant, there was commonly evidence of immunosuppression in the form of low presentation lymphocyte counts, advanced stage and systemic (B) symptoms. The results suggest that these patients have a propensity for lymphoproliferative disorders, possibly associated with some immune deficiency and the subsequent development of NHL is not treatment related. The findings also emphasise how important it is to biopsy recurrent disease.

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 Investigation's studies of Hodgkin's disease since 1970. PATIENTS: 2676 Patients entered into Hodgkin's 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 Hodgkin's disease. CONCLUSIONS: Avoidance of secondary leukaemia should be a minor factor in the choice of treatment for 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.