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 Hodgkin's disease in relation to age at treatment and other factors. PATIENTS AND METHODS: A cohort of 5,519 British patients with Hodgkin's 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 Hodgkin's 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 Hodgkin's disease require detailed investigation.

The follicular non-Hodgkin's lymphomas--I. The possibility of cure.

The follicular lymphomas pursue an indolent course in many patients. Long-term follow-up in large series is therefore necessary to establish whether cure is taking place, and if so, at what stage in the dissemination of the disease process it becomes unlikely. The time to, and site of relapse, together with its impact on survival has been studied in 398 patients entered into the British National Lymphoma Investigation limited and disseminated disease trials between 1974 and 1980. Relapse data were compared with various models to obtain maximum likelihood estimates of the proportions permanently remaining relapse-free following treatment. Long-term relapse-free survival was observed in 54.8 +/- 14.9% (95% CI) of patients at 15 years with Ann Arbor stage I disease, 29.2 +/- 13.6% in patients with stage II disease, 18.1 +/- 6.6% with stage III and 13.0 +/- 5.9% with IV disease. Relapse time-course data for all trial arms conform closely to lognormal distributions allowing maximum likelihood estimates of proportions remaining permanently relapse-free to be derived. Using this methodology, over a quarter of patients treated with involved radiotherapy alone or radiotherapy plus 6 months of chlorambucil in the limited disease (Ann Arbor stage I and II) trial are unlikely to relapse at any time in the future. Over 10% of patients treated in the disseminated disease trials with disease classified as Ann Arbor stage III are also statistically unlikely to relapse. The finding that a proportion of patients is statistically unlikely to experience a clinically obvious relapse is consistent with clinical cure. It is especially interesting that a small proportion of patients with disseminated disease and treated by chemotherapy have fallen into this category, but additional data are required to know at what point statistical cure becomes unlikely. Whether "clinical cure" is the same as "pathological cure" in this disease remains uncertain.

The follicular non-Hodgkin's lymphomas--II. Prognostic factors: what do they mean?

The Ann Arbor staging classification has long been recognised to have shortcomings when used to stage the follicular lymphomas. To date, the identification of important prognostic variables has not succeeded in producing a superior staging classification that reflects the stages of dissemination of these processes in a way that can be used in the testing of new therapeutic strategies. A fresh look is taken at these factors. Data from 398 patients entered into the British National Lymphoma Investigation trials between 1974 and 1980, were analysed to evaluate the performance of the Ann Arbor staging classification. Multiple regression and proportional hazards techniques were used to determine what factors independently influence response to initial treatment, the durability of that response and ultimate survival, and to isolate factors that relate to disease progression from those that have other mechanisms of action. The Ann Arbor staging classification fared poorly, minimally separating relapse-free and cause-specific survival probabilities in patients with the largest staging groupings, III and IV. Significant prognostic heterogeneity was seen in both of these stage groupings, with 22% of patients with stage IV disease on the basis of marrow involvement having slightly better outcomes than patients with stage III disease. Significant differences in outcome were also observed between patients of different age and sex in each Ann Arbor stage grouping. Increasing number of lymph node regions involved, constitutional symptoms, the presence of splenomegaly and increasing age were observed to have powerfully independent adverse influence on probability of complete response to treatment and cause-specific survival. The evolution of the follicular lymphomas is reflected at the clinical level by an increase in the number of lymph node regions involved and splenomegaly. Simple classifications based on simple counts of lymph node regions involved and splenomegaly are more successful than the Ann Arbor staging classification in subdividing the series into patient subgroups that, regardless of gender or age, experience significantly different probabilities of responding completely to therapy and, as a consequence, relapse-free and cause-specific survival expectations. The definition of poor prognosis in subgroups may be of value in selecting patients for newer and more intensive therapeutic approaches.

Variation in mantle technique: implications for establishing priorities for quality assurance in clinical trials.

74 European and American radiotherapists responded to a questionnaire investigating the treatment of a patient with stage IIA non-bulky Hodgkin's disease by mantle irradiation. A consensus was present for the dose aims to involved and uninvolved lymph nodes and the acceptable incidence of late normal tissue effects. There was less agreement as to the total dose and dose per fraction required to maintain normal tissue toxicity within the agreed acceptable incidence. Variation was found in the radiation technique employed, the amount of spinal cord shielding used, the prescription point, modifications if irradiation was given after chemotherapy, and the routine recording of dose and dose per fraction to the normal tissue at risk. This descriptive survey confirms the need for well designed quality assurance programmes and indicates the areas of particular uncertainty that currently exist.

Non-Hodgkin's lymphoma of the testis.

Primary non-Hodgkin's 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.

Idiopathic thrombocytopenic purpura in Hodgkin's disease: a report of eight cases.

Eight patients with idiopathic thrombocytopenic purpura (ITP) in association with Hodgkin's disease (HD) are reported from the British National Lymphoma Investigation (BNLI) registry. The patients were heterogeneous for initial stage of HD, histology and treatment received. The median time from diagnosis of HD to diagnosis of ITP was 23 months (range 3-57). Six of eight were in complete remission at diagnosis of ITP, one was in relapse, and one was undergoing first line chemotherapy. Of those patients developing ITP in remission, only one subsequently relapsed. The ITP responded in six of the eight patients to a single course of oral prednisolone. Thus the occurrence of ITP in patients with HD appears to be independent of the activity of the lymphoma, and responds to therapy as for primary ITP. The development of ITP in remission has no prognostic significance.

British National Lymphoma Investigation: pilot studies of neoadjuvant chemotherapy in clinical stage Ia and IIa Hodgkin's disease.

In order to improve treatment in early Stage IA and IIA Hodgkin's disease, the British National Lymphoma Investigation (BNLI) has evaluated two neoadjuvant chemotherapy regimens with involved field radiotherapy. This article reports the results of the methotrexate, vinblastine and prednisolone (MVP) study in 39 patients and updates the previous report on vinblastine, bleomycin and methotrexate (VBM) in 30 patients. Both studies recruited clinical Stage IA or IIA Hodgkin's disease patients with intermediate risk of relapse into a prospective multicentre Phase II study. They received two cycles of chemotherapy followed by involved field radiotherapy and then four further cycles of chemotherapy. For MVP the 5-year survival is 97% and for VBM it is 93%. The 5-year event-free survival rates are 71% and 87% respectively. The acute pulmonary and haematological toxicity occurring with VBM was not acceptable and therefore the MVP study was performed. There was less toxicity with this regimen although modest acute pulmonary toxicity was still observed. However, in view of the length of treatment with MVP (9 months) and the excellent results reported by the Manchester group, future efforts of the BNLI are to be directed towards a new short course chemotherapy regimen, VAPEC-B (vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin).

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-Hodgkin's 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.

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.

Risk of second primary cancers after Hodgkin's disease by type of treatment: analysis of 2846 patients in the British National Lymphoma Investigation.

OBJECTIVE: To analyse the risk of second primary cancers during long term follow up of patients with Hodgkin's disease. DESIGN: Cohort study. SETTING: The British National Lymphoma Investigation (a collaborative group of over 60 participating centres in Britain treating lymphomas). PATIENTS: 2846 patients first treated for Hodgkin's disease during 1970-87, for whom follow up was complete in 99.8%. MAIN OUTCOME MEASURES: Second primary cancers; uniform pathology reviews confirmed the diagnosis of Hodgkin's disease and of second primary non-Hodgkin's lymphomas. RESULTS: 113 second primary cancers occurred. Relative risk of cancer other than Hodgkin's disease was 2.7 (95% confidence interval 2.3 to 3.3) compared with the general population, with significant risk of leukaemia (16.0(9.1 to 26.0)); non-Hodgkin's lymphoma (16.8(9.8 to 26.9)); and cancers of the colon (3.2 (1.4 to 6.2)), lung (3.8 (2.6 to 5.4)), bone (15.1 (1.8 to 54.7)), and thyroid (9.4 (1.1 to 33.9)). Absolute excess risk associated with treatment was greater for solid tumours than for leukaemia and lymphomas. Relative risk of leukaemia increased soon after treatment, reaching a peak after five to nine years. It was increased substantially after chemotherapy (27.9 (12.7 to 52.9)), combined treatment with radiotherapy and chemotherapy (21.5 (7.9 to 46.8)), and relative to number of courses of chemotherapy but was not significantly increased after radiotherapy (2.5 (0.1 to 14.1)). Relative risk of non-Hodgkin's lymphoma increased in the first five years after treatment and remained high but showed no clear relation with type or extent of treatment. Relative risk of solid tumours was less raised initially but increased throughout follow up and for lung cancer 10 years or more after entry was 8.3 (4.0 to 15.3). The risk of solid tumours increased after treatments including radiotherapy and after chemotherapy alone. The risk after chemotherapy increased significantly with time since first treatment. CONCLUSION: The risk of solid cancer, not of leukaemia, is the major long term hazard of treatment for Hodgkin's disease, and this seemed to apply after chemotherapy as well as after radiotherapy. These risks of second cancers are important in choice of treatment and in follow up of patients, but they are small compared with the great improvements in survival which have been brought about by modern therapeutic methods for Hodgkin's disease.

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.

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.

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.

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.

Mitoxantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high-grade lymphoma: results of a BNLI randomized trial of PAdriaCEBO versus PMitCEBO.

A prospective, multicenter, randomized trial was undertaken to compare the efficacy and toxicity of adriamycin with mitoxantrone within a 6-drug combination chemotherapy regimen for elderly patients (older than 60 years) with high-grade non-Hodgkin lymphoma (HGL) given for a minimum of 8 weeks. A total of 516 previously untreated patients aged older than 60 years were randomized to receive 1 of 2 anthracycline-containing regimens: adriamycin, 35 mg/m(2) intravenously (IV) on day 1 (n = 259), or mitoxantrone, 7 mg/m(2) IV on day 1 (n = 257); with prednisolone, 50 mg orally on days 1 to 14; cyclophosphamide, 300 mg/m(2) IV on day 1; etoposide, 150 mg/m(2) IV on day 1; vincristine, 1.4 mg/m(2) IV on day 8; and bleomycin, 10 mg/m(2) IV on day 8. Each 2-week cycle was administered for a minimum of 8 weeks in the absence of progression. Forty-three patients were ineligible for analysis. The overall and complete remission rates were 78% and 60% for patients receiving PMitCEBO and 69% and 52% for patients receiving PAdriaCEBO (P =.05, P =.12, respectively). Overall survival was significantly better with PMitCEBO than PAdriaCEBO (P =.0067). However, relapse-free survival was not significantly different (P =.16). At 4 years, 28% of PAdriaCEBO patients and 50% of PMitCEBO patients were alive (P =.0001). Ann Arbor stage III/IV, World Health Organization performance status 2-4, and elevated lactate dehydrogenase negatively influenced overall survival from diagnosis. In conclusion, the PMitCEBO 8-week combination chemotherapy regimen offers high response rates, durable remissions, and acceptable toxicity in elderly patients with HGL.

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 Hodgkin's 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 Hodgkin's 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 Hodgkin's disease. High doses facilitated by ABMT can lead to better disease-free survival.

ChlVPP alternating with PABlOE is superior to PABlOE alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation/Central Lymphoma Group randomized controlled trial.

The purpose of this randomized trial was to compare the efficacy of 6 cycles of prednisolone, Adriamycin (doxorubicin), bleomycin, vincristine (Oncovin) and etoposide (PABlOE) with 3 cycles of PABIOE that alternate with 3 cycles of chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) in patients with advanced Hodgkin's disease. Between October 1992 and April 1996, 679 patients were entered onto the study. 41 of these did not match the protocol requirements on review and were excluded from further analysis, most of these being reclassified as NHL on histological review. Of the remaining 638 patients, 319 were allocated to receive PABIOE and 319 were allocated to receive ChlVPP/PABlOE. The complete remission (CR) rates were 78% and 64%, for ChlVPP/PABlOE and PABIOE respectively after initial chemotherapy (P< 0.0001). 124 patients were re-evaluated subsequently following radiotherapy to residual masses. The CR rates changed from 78% to 88% for ChlVPP/PABlOE and from 64% to 77% for PABlOE when re-evaluated in this manner (treatment difference still significant, P = 0.0002). The treatment associated mortality in the PABlOE arm was 2.2% (7 deaths), while there were no such deaths in the ChlVPP/PABlOE arm (P = 0.015). The failure-free survival was significantly greater in the ChlVPP/PABlOE arm (P< 0.0001) as was the overall survival (P = 0.01). The failure-free and overall survival rates at 3 years were 77% and 91% in the ChlVPP/PABlOE arm, compared with 58% and 85% in the PABIOE arm, respectively. These results indicate that ChlVPP alternating with PABIOE is superior to PABIOE alone as initial treatment for advanced Hodgkin's disease.