Trial Design. Journal of Clinical Oncology, Vol 10, No 8 (August), 1992: pp

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1 Alternating With EVAP Is Superior to Alone in the Initial Treatment of Advanced Hodgkin's Disease: Results of a British National Lymphoma Investigation Trial By B.W. Hancock, G. Vaughan Hudson, B. Vaughan Hudson, M.H. Bennett,t K.A. MacLennan, J.L. Haybittle, L. Anderson, and D.C. Linch Purpose: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone () with four cycles of 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, and 299 were allocated to receive /EVAP. Results: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NSI), and 65% and 75%, respectively, after the subsequent administration of radiother- IT IS NOW MORE than 20 years since cyclical combination chemotherapy (mustine [mechlorethamine], vincristine or vinblastine, procarbazine, and prednisolone [MOPP or MVPP]) was established as an effective treatment for advanced Hodgkin's disease. 1,2 Long-term survival is observed in approximately one half of the patients treated with these regimens. 3,4 However, mustine produces marked nausea, vomiting, and phlebitis, which often result in considerable morbidity, and sometimes in chemotherapy dose modification and delays and poor patient compliance. The substitution of oral chlorambucil (ChLVPP or ) shows similar long-term results, although with less acute toxicity. 5,6 From the Yorkshire Cancer Research Campaign, Department of Clinical Oncology, Weston Park Hospital, Sheffield; Department of Pathology, Mount Vernon Hospital, Northwood; Department of Oncology, University College and Middlesex School of Medicine, London; Department of Pathology, Royal Marsden Hospital, London; and Department of Haematology, University College and Middlesex School of Medicine, London, United Kingdom. Submitted January 21, 1992; accepted April 15, Supported by the Cancer Research Campaign. Additional support was obtained from the Lymphoma Research Fund, the Lisa Lear Fund, and the Isle ofman Anti-CancerAssociation. fdr M.H. Bennett is deceased. Address reprint requests to G. Vaughan Hudson, MD, British National Lymphoma Investigation, Department of Oncology, 7he Middlesex Hospital, Mortimer Street, London WIN 8AA, United Kingdom by American Society of Clinical Oncology X/92/ $3.00/0 apy to residual masses (P <.01). The procedure associated mortality in the and /EVAP arms was 1% and 3%, respectively. The actuarial CR relapsefree survival was significantly greater in the /EVAP arm (P <.001) as was the overall survival (P <.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 arm, compared with 72%, 47%, and 75% in the /EVAP arm, respectively. Conclusion: These results indicate that and EVAP is superior to alone as initial treatment for advanced Hodgkin's disease. J Clin Oncol 10: c 1992 by American Society of Clinical Oncology. Santoro et a1 7 reported the superiority of an alternating regimen (Adriamycin [doxorubicin; Familitalia Carlo Erba, Ltd, United Kingdom], bleomycin, vinblastine, and dacarbazine [MOPP/ABVD]) designed in accordance with the Goldie and Coldman hypothesis. 8 Longterm follow-up of these patients confirms the advantage for MOPP/ABVD. 9 Other studies of single regimens compared with alternating regimens have produced conflicting results Therefore, between 1983 and 1989, the British National Lymphoma Investigation (BNLI) conducted a randomized multicenter study of initial treatment with versus alternating with etoposide, vinblastine, Adriamycin, and prednisolone (EVAP). The aim of the trial was to compare the efficacy of the two regimens in the induction of complete remission (CR), relapsefree survival, and, ultimately, overall survival in patients with advanced Hodgkin's disease at presentation, which was defined as stages IB, IIB, and III/IV. Trial Design PATIENTS AND METHODS The criteria for inclusion were as follows: age of more than 15 years; opportunity for adequate long-term follow-up must have been anticipated; freedom from any other known serious disease that might limit severely the patient's life expectancy; no previous chemotherapy and or radiotherapy (RT) except as an emergency measure for obstructive symptoms; surgical staging was not required, but all patients were required to have either lymphangiography or computed tomographic (CT) scanning of the abdomen; histopathologic diagnosis confirmed by the BNLI histopathology panel; and informed consent obtained Journal of Clinical Oncology, Vol 10, No 8 (August), 1992: pp

2 v /EVAP FOR HODGKIN'S DISEASE Table 1. Treatment Protocols Chlorambucil 10 mg orally day 1-10 Vincristine 1.4 mg/m2 (maximum, 2 mg) intravenously day Procarbazine 100 mg/m2 (maximum, 200 mg) orally day I - 10 Prednisone/prednisolone 25 mg/m 2 (maximum, 60 mg) orally day 1-14 EVAP Etoposide 150 mg/m 2 (maximum, 200 mg) orally day 1-3 Vinblastine 6 mg/m 2 (maximum, 10 mg) intravenously day Doxorubicin 25 mg/m2 intravenously day Prednisone/prednisolone 25 mg/m 2 (maximum, 60 mg) orally day 1-14 NOTE. Patients received either eight courses of given at 4-week intervals or four courses of that alternated with four courses of EVAP given at 4-week intervals. A total of 594 patients were entered onto this trial between June 1983 and December Patients were randomized to receive either (295) or alternating with EVAP (299). Randomization was performed after stratification for age (< 50 years v > 50 years of age) and stage (IB/IIB v IIIiIV). Staging was performed according to the Ann Arbor criteria and histologic grading was performed according to previously published BNLI criteria.15 Treatment Regimen dosages are listed in Table 1. They were based on previous BNLI experience of toxicity, and were chosen to allow cycles to be given as rapidly and with as little dose reduction as possible. The doses of vincristine, vinblastine, procarbazine, and etoposide included a maximum limit such that the dose per surface area was only relevant to small patients. Patients were completely reassessed after four cycles of chemotherapy. If the patient was in clinical CR at this time, four additional cycles of chemotherapy were scheduled (ie, a total of eight cycles). If after four cycles the assessment showed the patient to be progressively improving, then the treatment was scheduled to continue (provided that progressive improvement persisted) until a clinical CR was attained, after which four more cycles of chemotherapy were scheduled (ie, a total of 10 cycles for a patient in clinical CR after the sixth cycle). If there was progressive disease, no progressive improvement, or disease relapse then the treatment was changed. The number of cycles given in the two arms is shown in Fig 1. Fewer patients in the arm received eight or more courses because the response rate was lower than in the /EVAP arm (see Results). Patients with bulky mediastinal disease at presentation (defined as a mass > one third of the widest diameter of the chest on x-ray) were permitted to receive initial treatment with RT to the site of bulk disease in addition to their chemotherapy. Patient Characteristics Both arms of the trial were well balanced for all characteristics, except for the fact that there were more patients with a low presenting lymphocyte count in the arm (Table 2). Definitions and Data Analysis CR was defined as complete disappearance of all disease for a minimum of 3 months after the completion of therapy. CR rates 1253 were compared in the two arms of the trial by use of a X 2 test with Yates correction.16 Survival curves were calculated by the life-table method and statistical comparison of curves were performed by the log-rank test as described by Peto et al.17 The data included follow-up to November CR rate, CR relapse-free survival, and disease-free survival (DFS) refer to states that result solely from the use of initial treatment alone. CR relapse-free survival refers only to those patients who achieved CR at the end of their initial chemotherapy, and was used to denote the actuarial percentage of patients who were alive and had remained free from Hodgkin's disease to the time specified. DFS was used to denote the actuarial percentage of all the patients in the group in question who were alive and had remained free from Hodgkin's disease to the time specified. The prognostic effects of initial treatment and of the patient characteristics on the CR rate were analyzed by means of multivariate analysis that involved a logistic regression model.' 8 The DFS and overall survival were analyzed by means of the proportional hazards model.19 The influence of prognostic factors was analyzed on follow-up to March Initially, the analyses were performed on the patients in both arms of the trial together, which included treatment allocation as a prognostic factor. They were then repeated on each arm separately to determine the factors in each arm that were most important, ie, those with a regression coefficient more than 1.96 times its SE. Finally a model made up of these factors was fitted to the data in each arm separately so that the regression coefficients for each factor could be compared between the two arms and the statistical significance of any difference be determined. RESULTS Overall Response to First-Line Therapy Overall, of the 295 patients randomized to receive, 169 (57.3%) achieved CR. Ten patients in this arm (3%) received mediastinal RT as planned initial treatment in addition to their chemotherapy because of bulk disease at presentation. Two more patients who died of therapy-related causes (one infection, one pneumonitis of uncertain cause) were in remission at the time of death but were considered to be nonresponders as were three patients who died early in the course of 0O a 100 = ýtm /EVAP 80 soo o Fig NUMBEROFCOURSES The number of cycles of chemotherapy received in each arm.

3 1254 HANCOCK ET AL Table 2. Characteristics of 594 Patients Entered Onto Versus II L 1 I because of bulk disease at presentation. A further two LOP Anemrnating wltn var Trial patients died from therapy-related causes (one infec- Alternating Unknown tion, one hepatitis) with no evidence of Hodgkin's With EVAP With EVP Values disease, and two other patients died during therapy (one No. No. % septicemia, one cerebrovascular accident) without the No. of patients status of their Hodgkin's disease being determined. One Age, years Median patient developed abnormal liver function tests after the Range, years first course of therapy and was changed to an alternative < regimen; although he attained a CR on this treatment, > he was considered a non-cr to /EVAP. The difference between the CR rates for and / EVAP was not statistically significant. In 33 patients in the arm and 45 patients in the /EVAP arm, RT was given to residual masses at the end of chemotherapy. Twenty-two and 32 patients, respectively, achieved a CR. The overall CR rates were % and 75%, respectively, (P <.01) for the and /EVAP arms when the CRs produced by local RT were included The overall CR relapse-free survival for the two arms is shown in Fig 2. At 5 years, the actuarial CR relapse- Sex Male Female Stage IB 118 IIIA IIIB IVA IVB Total with B symptoms Mediastinal involvement Pathology LP I Grade I NSI NSII MC Grade II LD Albumin < 36 g/l > 36 + g/l Hemoglobin < 12 g/dl > 12+g/dL ESR < Lymphocyte count < 1.5 x 10 9 /L > 1.5 x 10 9 /L free survival in the arm was 52% and in the /EVAP arm was 72% (P <.001). The overall DFS is shown in Fig 3. The actuarial DFS at 5 years was % in the arm and 47% in the /EVAP arm t lne overall survival in the two arms is snown in rig,. 5 At 5 years the actuarial survival in the arm was 66% and in the /EVAP arm was 75% (P <.05). Protocol Violations Major protocol violations occurred in 14 patients (2%); two were in the arm (received / 13* EVAP) and 12 in the alternating EVAP arm, 10 8 too Abbreviations: LP, lymphocyte predominance; NSI, nodular sclerosis grade 1; MC, mixed cellularity; LD, lymphocyte depletion; ESR, erythrocyte sedimentation rate. *A number of ESR values are unavailable because several centers now only measure plasma viscosity. "There is an imbalance in the two arms with regard to presentation lymphocyte count (P =.02) B treatment (one gastrointestinal hemorrhage, one myocardial infarct, and one cerebrovascular accident). The status of their Hodgkin's disease at the time of death was unknown. Overall, of the 299 patients who were randomized to receive /EVAP, 192 (64.2%) achieved CR. Sixteen of these patients (5%) received RT as planned initial treatment in addition to their chemotherapy? 1 ME II (YEARS) Fig 2. The actuarial CR relapse-free survival of patients who were treated with (A) /EVAP (N = 192) and (B) (N = 170). X 2 = 10.04; P = I a

4 v /EVAP FOR HODGKIN'S DISEASE o 2 - ll IL... A B Table 3. Incidence of WHO Stage 3/4 Toxicity alt EVAP (%) (%) Hematologic Infections 4 21 Gastrointestinal 8 12 Neurologic 5 4 Alopecia 6 58 Skin < TINE YEAR$SI tion on two or more occasions) or delays in start of a S i course of treatment (> 1 week on two or more occasions) were required (usually on the basis of myelosup- pression) in 37 (13%) patients who received and 295). in 50 (17%) patients who received /EVAP. Fig 3. The actuarial DFS of patients w ho were treated with (A) /EVAP (N = 299) and (B) (N = of whom received alone. When this 2% of patients were excluded from the analysis, there was no change in the conclusions to be drawn about the comparison of CR, relapse, DFS, and overall survival rates between the two arms. Toxicity Mortality Death in both groups was related mostly to disseminated Hodgkin's disease. There has been a total of 89 deaths in the arm and 67 deaths in the / EVAP arm (Table 5). A total of seven patients died from second malignancy in the arm (five bronchial carcinoma, two non-hodgkin's lymphoma); none died in the /EVAP arm. Prognostic FactorAnalysis The prognostic factors found to be independently significant are listed in Table 6 for both arms combined, and also for each arm separately. CR rate. The most important factors related to CR rate in the trial overall were mediastinal status, albumin level, and hemoglobin level. These factors included the Pvalue (.15) for the effect of treatment allocation. There were three (1%) early deaths that were probably related to treatment in the arm and 10 (3%) treatment-related deaths in the /EVAP arm. The incidence of treatment-related toxicities in the two arms is listed in Table 3 and the definition for stage 3 and 4 toxicity in Table 4. Full toxicity data are available for only 376 patients in the later part of the trial. It is apparent that /EVAP results in greater alopecia, and in more hematologic suppression and infection. Major dose modifications (> half-dose reduco$0 Table 4. Definition of Stage 3 and 4 Toxicity Stage 3 4 so 4 a 2 0 TIME M {YEARS) E A Fig 4. The actuarial overall survival curves of patients who were treated with (A) /EVAP (N = 299) and (B) (N = 295).? = 3.954; P = Hematologic Hemoglobin (g/dl) < 6.5 WBC count (10 9 /L) < 1.0 Platelets (10 9 /L) < 25 Gastrointestinal Oral Ulcers (liquids only) Alimentation impossible Nausea/vomiting Vomiting requiring Intractable vomiting treatment Diarrhea Intolerable requiring Hemorrhagic dehydratreatment tion Neuropathy Severe sensory Paralysis and/or motor Skin Moist desquamation Exfoliative dermatosis Infection Major Life-threatening with (specify site) hypotension

5 1256 Table 5. Causes of Death /EVAP Hodgkin's disease-related Treatment-related 3 10 Second malignancy 7 0 (5 CaB, 2 NHL) Other 8 2 Total Abbreviations: CaB, carcinoma of the bronchus; NHL, non-hodgkin's lymphoma. In the arm the most important factors were mediastinal involvement, albumin level, and hemoglobin level; in the /EVAP arm the only factor found to be important was clinical stage. When only patients of the NS histopathologic subtype were analyzed, grade was an additional important factor (P =.03). CR relapse-free survival. The most important factors related to CR relapse-free survival in the trial overall were the initial treatment allocated and the erythrocyte sedimentation rate (ESR). The P value for treatment allocation was.001 in favor of /EVAP, and was.007 when deaths the result of causes other than Hodgkin's disease were censored. In the arm, the only significant factor (P >.05) was the lymphocyte count; in the /EVAP arm no factor was significant. The difference between the coefficients for the effect of the lymphocyte count in the two arms was significant at the P =.05 level. Overall survival. The most important factors related to survival in the trial overall were age, ESR, and albumin level; stage was significant when deaths from causes other than Hodgkin's disease were censored. In the arm the most important factors were Table 6. Factors Associated With Good Prognosis Alternating With Overall Arm EVAP Arm CRRate Hb > 12 g/dl Hb > 12 g/dl Stage III/IV Alb > 35 g/l Alb > 35 g/l Med negative Med negative CR relapse- Randomization free survival to alternating EVAP ESR < 60 mm Lym > 1.5 x 10 9 /L - Overall sur- Age < 50 years Age < 50 years Age < 50 vival years Albumin > 35g/L Albumin > 35 g/l Stagel/ll ESR < 60 mm ESR < 60 mm Pathology grade I Abbreviations: Alb, albumin; Med, mediastinum. HANCOCK ET AL age, ESR, and albumin level; in the /EVAP arm, they were age, stage, and pathologic grade. DISCUSSION This trial showed that the alternating regimen of /EVAP resulted in a higher CR rate than, although this was only significant if assessment was made after patients with a partial response had received subsequent RT. /EVAP also resulted in a significant improvement in DFS and overall survival. These results are in accord with the original studies from Milan that compared MOPP and MOPP/ABVD regimens, 7 and with the Cancer and Leukemia Group B trial (8251)14; for freedom from progression, the present results are in accord with the European Organization for Research and Treatment of Cancer (EORTC) trial. 13 The CR rates reported here with are lower than the remission rates reported from some other centers especially in nonrandomized trials. Several explanations for this require consideration. First, the BNLI definition of CR required the absence of disease for 3 months after the initial treatment was completed. Although more stringent than most trial end points, this is unlikely to account for such differences because early relapse in the first 3 months after completion of therapy is unusual. Second, the lower CR rate could relate to the lower dose intensity in the regimen compared with the original National Cancer Institute (NCI) MOPP regimen. 3 The CR rate observed here with in stage III/IV patients was 57%, which is in accord with our previous experience in a randomized trial in which was equivalent to MOPP, the latter also given in reduced doses. 6 It is of particular interest that in the total BNLI experience of MOPP (at reduced doses), the CR rate was 63%, which is lower than the 84% achieved with full-dose MOPP at the NCI, but the overall survival at 10 years was virtually identical at 51%.4 The CR rate in this trial for stage IIIB/IV patients was 55% for and 60% for /EVAP, which is almost identical to the results achieved with either MOPP (full-dose) or MOPP/ABVD (57% and 55%, respectively) in a similar group of patients who were treated in an European Organization of Research and Treatment of Cancer (EORTC) randomized trial.' 3 It seems likely that many of the differences in CR rates relate to patient selection, and this emphasizes the importance of randomized trials to evaluate different therapies. Although this trial was designed on the basis of the Goldie and Coldman hypothesis, it cannot be concluded that the improved results were caused by the alternating regimen. It is possible that the improvement relates to

6 v /EVAP FOR HODGKIN'S DISEASE the use of anthracyclines, etoposide, or the use of both in the EVAP regimen, rather than the introduction of multiple agents into the total regimen. The /EVAP regimen was more myelotoxic than the -alone arm, and it is also possible that if the doses were titrated up to a level of myelosuppression similar to that observed in the /EVAP arm, then the different responses between the two arms would not be apparent. It is noteworthy that in the CALGB (8251) trial, in which there was a three-way randomization of MOPP versus MOPP/ABVD versus ABVD, the ABVD proved as effective as MOPP/ABVD and was superior to MOPP.1 4 EVAP differs from ABVD in that there is no dacarbazine in EVAP and the bleomycin is replaced by etoposide. EVAP has not been tested formally against MOPP or in a randomized trial, but this clearly merits further investigation. RT to residual masses was given to 11% of patients in the arm and to 15% of patients in the / EVAP arm. This difference was not significant, and the slightly more frequent use of RT in the /EVAP arm was in accord with the higher response rate in this arm, which was likely to translate to more patients with residual disease in only one site. However, it must be acknowledged that the use of subsequent RT does confound the comparison of the two chemotherapy regimens. For this reason, the CR rate before consolidation RT is given and the CR DFS refer only to those patients who did not receive subsequent consolidation RT. The alternating /EVAP regimen had more immediate toxicity than alone. There were three treatment-related deaths in the arm (1%) and 10 (3%) in the /EVAP arm. This mortality of 3% is in line with other regimens, however, and is probably an acceptable figure. The increased number of treatmentrelated deaths in the /EVAP arm was predominantly the result of increased myelosuppression. When the trial was opened, detailed toxicity was not recorded. Such information was only available on the later 346 patients. It is seen listed in Table 3, and is obvious that World Health Organization stage 3 and 4 hematologic toxicity was more than twice as common in the / EVAP arm compared with the arm. The severe infection rate was also correspondingly higher in the /EVAP arm. It is of interest that there have been no second malignancies to date in the /EVAP arm compared with seven in the arm. It is tempting to speculate 1257 that this is because of the lower dosage of alkylating agent (chlorambucil) delivered in the alternating regimen, a member of a group of compounds known to be carcinogenic in animal studies. 20 Clearly a longer follow-up is required to confirm this. As expected, multivariate analysis of the trial overall showed that patients with mediastinal disease or with a low presentation albumin or hemoglobin, had a lower CR rate. This is in accord with previous data. 21, 22 (It should be noted that this trial commenced in 1983, and, at that time, the LDH level at presentation and the measurement of tumor bulk were not recorded. Thus, these parameters were not available for analysis). Once remission was obtained, the above parameters did not predict relapse rate. In the /EVAP arm, no characteristic was identified as a predictor of relapse, whereas in the arm, a low lymphocyte count at presentation was associated significantly with disease recurrence. Thus it seems that the low lymphocyte count identifies a particular subgroup of patients for whom initial treatment with alone was inadequate. A relationship between presentation lymphocyte count and DFS in stage IV patients has been reported previously, 23 and also for Hodgkin's disease patients overall and IIIB/IV patients in particular in relation to overall survival. 24,25 This factor was not prognostic for CR rate, further suggesting that the biologic processes involved in the attainment of CR may be sometimes different from those involved in its maintenance. The overall survival of patients in the trial was related only in part to the initial treatment that they received because patients in whom the latter failed to achieve and to maintain freedom from disease received further (salvage) treatment. This treatment was not randomized between the two arms of the trial, and was comprised of a variety of different regimens. These consisted of EVAP, which was given to approximately 50% of the failures in the arm; of RT alone; of intensive chemotherapy that consisted of a combination of carmustine, etoposide, cytarabine, and melphalan (BEAM) in conjunction with autologous bone marrow transplant rescue (ABMT); and of a variety of other chemotherapy regimens. Assessment of overall survival is further complicated by the occurrence of deaths that were the results of causes other than Hodgkin's disease, but that may (or may not) have been caused by long-term toxic effects of initial (or salvage) treatment. The occurrence of such deaths inevitably increases with time. These factors, in conjunction with the relatively short time for which the trial has been in existence preclude any

7 1258 detailed statistical analysis of the relationship between salvage therapy and overall survival at present. In conclusion, initial treatment with /EVAP resulted in a significantly higher CR relapse-free survival and higher DFS, and also a suggestion of a real improvement in overall survival, compared with alone, with only a modest increase in toxicity. ACKNOWLEDGMENT HANCOCK ET AL The BNLI would like to acknowledge the enthusiastic support of collaborators from referring centers whose patients are included in this analysis, J. Bonner for data collection and management, and S.P. Ray for typing the manuscript. J.L.H. is indebted to the Medical Research Council Cancer Trials Office, Cambridge, for the use of computer facilities. REFERENCES 1. De Vita VT, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of Hodgkin's disease. Ann Intern Med 73: , Nicholson WM, Beard MEJ, Crowther D, et al: Combination chemotherapy in generalised Hodgkin's disease. Br Med J 3:7-10, Longo DL, Young RC, Wesley M, et al: Twenty years of MOPP therapy for Hodgkin's disease. J Clin Oncol 4: , Linch DC, Vaughan Hudson B: Management of the Malignant Lymphomas, in Hoffbrand AV (ed): Recent Advances in Haematology. London, UK, Longman Group, 1988, pp Selby P, Patel P, Milan S, et al: ChlVPP combination chemotherapy for Hodgkin's disease; long term results. Br J Cancer 62: , Hancock BW, Vaughan Hudson G, Vaughan Hudson B, et al: British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against (Leukeran substituted for mustine), in advanced Hodgkin's disease-long term results. Br J Cancer 63: , Santoro A, Bonadonna G, Bonfante V, et al: Alternating drug combinations in the treatment of advanced Hodgkin's disease. New Engl J Med 306: , Goldie JH, Coldman AJ: The genetic origin of drug resistance in neoplasms; implications for systemic therapy. Cancer Res 44: , Santoro A, Bonfante V, Viviani S, et al: Decrease in mortality rate by Hodgkin's disease (HD) after ABVD vs MOPP: 10-year results. Proc Am Soc Clin Oncol 10:281, 1991 (abstr 982) 10. Jones SE, Haut A, Weick JK, et al: Comparison of Adriamycin-containing chemotherapy (MOP-BAP) with MOPP-bleomycin in the management of advanced Hodgkin's disease. Cancer 51: , Gams RA, Omura GA, Velez-Garcia E, et al: Alternating sequential combination chemotherapy in the management of advanced Hodgkin's disease. Cancer 58: , Vinciguerra V, Propert KJ, Coleman M, et al: Alternating cycles of combination chemotherapy for patients with recurrent Hodgkin's disease following radiotherapy-a prospectively randomized study by the Cancer and Leukemia Group. Br J Clin Oncol 4: , Burgers JMV, Somers R, Henry-Amar M, et al: Management of relapse and survival in advanced stage Hodgkin's disease: The EORTC experience. Ann Oncol 2:63-66, 1991 (suppl 2) 14. Canellos GP, Propert K, Cooper R, et al: MOPP vs. ABVD vs. MOPP alternating with ABVD in advanced Hodgkin's disease: A prospective randomised CALGB trial. Proc Am Soc Clin Oncol 7: , 1988 (abstr 888) 15. Bennett MH, MacLennan KA, Vaughan Hudson B, et al: The Clinical and Prognostic Relevance of Histopathological Classification in Hodgkin's Disease, in Fenoglio-Preiser CM, Wolff M, Rilke F (ed): Progress in Surgical Pathology. New York, NY, Field and Wood, 1989, pp Yates F: Contingency tables involving small numbers and the X 2 test. J R Stat Soc 1: , 1934 (suppl) 17. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomised clinical trials requiring prolonged observations of each patient: II. Analysis and examples. Br J Cancer 35:1-39, Altman DE: Practical Statistics for Medical Research. London, UK, Chapman and Hall, 1991, pp Cox DR: Regression models and life tables. J R Stat Soc (Series B) 34: , IARC: Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, vol 9. Some azirdines, N- S- and O-mustards and sclenium. IARC. Lyon (1975) 21. Anderson H, Jenkins JPR, Brigg DJ, et al: The prognostic significance of Mediastinal Bulk in patients with Stage IA-IVB Hodgkin's Disease: A report from the Manchester Lymphoma Group. Clin Radiol 36: , Vaughan Hudson B, MacLennan KA, Bennett MH, et al: Systemic disturbance in Hodgkin's disease and its relation to histopathology and prognosis (BNLI Report No. 30). Clin Radiol 38: , Specht L, Nissen NI: Prognostic factors in Hodgkin's disease stage IV. Eur J Haematol 41: , MacLennan KA, Vaughan Hudson B, Jelliffe AM: The pretreatment blood lymphocyte count in 1100 patients with Hodgkin's disease: The prognostic significance and the relationship to the presence of systemic symptoms. Clin Oncol 7: , Wagstaff J, Gregory WM, Swindell R, et al: Prognostic factors for survival in stage IIIB and IV Hodgkin's disease: A multivariate analysis comparing two specialist treatment centres. Br J Cancer 58: , 1988