Radiotherapy versus combined modality in early stages

Annals of Oncology 3 (Suppl. 4): S77-S81, 1992. C 1992 Klmver Academic Publishers. Printed in the Netherlands.

Original article Radiotherapy versus combined modality in early stages L. Specht,1 P. Carde,2 P. Mauch,3 S. M. Magrini4 & M. T. Santarelli5 x

Herlev University Hospital, Copenhagen, for the International Hodgkin's Disease Collaborative Croup, Copenhagen and Oxford Universities, Denmark and the U.K.; 2lnstitut Custave-Roussy, Villejuif France; 'Joint Center for Radiation Tlterapy, Harvard Medical School, Boston, U.S.A.; * University of Florence, for the Radiotherapy and Haematology Departments of Florence and Rome Universities, Italy; ""GATLA, Buenos Aires, Argentina

that by careful staging and selection of patients and by careful radiotherapy techniques the number of patients exposed to potentially toxic chemotherapy may be kept at a minimum. Recently, trials have been carried out testing chemotherapy alone. The results of these trials are however conflicting. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should be carefully tested in large randomized trials before being implemented for genera] clinical use.

Introduction

Trials of radiotherapy versus combined modality treatment in early stages1

In early stage Hodgkin's disease both megavoltage radiotherapy and combination chemotherapy are effective treatment modalities. The optimal choice of treatment or combination of treatments for the individual patient is still debated. The large International Database on Hodgkin's Disease contains data on a total of 8,284 clinically staged early stage patients treated since 1970 in 20 different centres in Europe and America [1]. More than half of these patients were treated initially with radiotherapy alone, most of the remaining patients were treated with combined modality treatment, and only a small number were treated with chemotherapy alone. The 5- and 10-year survival of these patients is around 90% and 80%, respectively. Most of the deaths are due to Hodgkin's disease, but some are related to either acute or long-term adverse effects of treatment. Although the results of modern treatment are good, still 1 in 5 of patients in early clinical stages will be dead within 10-20 years of diagnosis. There is thus both a need for, and room for, improvement. The challenge is to attain an improvement in the effectiveness of the treatment of Hodgkin's disease, and at the same time to decrease the risks of significant acute and longterm toxicities. How this is to be achieved is still unresolved. Various treatment approaches have been tested, and different groups and centres advocate varying treatment policies for early stage patients.

Key words: chemotherapy, combined modality treatment, early stage, Hodgkin's disease, metaanalysis, radiotherapy

Twenty-two randomized trials of radiotherapy alone versus radiotherapy plus adjuvant combination chemotherapy in early stage Hodgkin's disease have been carried out worldwide. Most of these trials have long follow-up and have been published [2-16]. The majority were large enough to show that the addition of combination chemotherapy at the time of the initial radiotherapy significantly improves recurrence free survival. However, because of the success of salvage chemotherapy for relapse after initial treatment with irradiation alone, none of these individual trials have demonstrated any clear improvement in overall survival by the addition of prophylactic chemotherapy up front. Any reduction in mortality produced by the prophylactic use of chemotherapy is thus likely to be of moderate size. To detect reliably any moderate improvement in overall survival, a much larger number of patients is needed than was entered into any one of these trials. At the Second International Symposium on Hodgkin's Disease in Cologne in October 1991 the preliminary results of a worldwide metaanalysis, organized by Copenhagen and Oxford Universities, of all 1

Specht L. Radiotherapy vs combined modality in stages I-IIIA overview. Second International Symposium on Hodgkin's Disease, Cologne, October 3 - 5 , 1991.

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Summary. In early stage Hodgkin's disease the optimal choice of treatment for the individual patient is still an unresolved issue. So far, twenty-two randomized trials of radiotherapy alone versus radiotherapy plus combination chemotherapy have been carried out worldwide. The preliminary results of a global metaanalysis of these trials indicate that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front improves survival. Arguments in favour of the addition of chemotherapy up front are: that laparotomy may be avoided, that radiation fields and doses may perhaps be reduced, and that the stress of experiencing a relapse is avoided in many patients. The major argument against the use of chemotherapy up front is:

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Arguments in favour of the use of chemotherapy in the intial treatment of early stage disease2 The EORTC pioneered the use of adjuvant chemotherapy in early stage disease when the HI trial [17], employing 2 years of adjuvant therapy with vinblastine, was initiated by Professor Tubiana almost 30 years ago. As in later trials, the employment of adjuvant chemotherapy improved recurrence free survival, but this was not reflected in a statistically clear survival advantage (5,18]. One advantage of using chemotherapy up front would be that staging laparotomy with its morbidity and risk of complications could be avoided. In the H2 trial of the EORTC [19] patients were randomized between spleen irradiation and splenectomy. All patients were treated with mantle and paraaortic irradiation, and patients with mixed cellularity or lymphocytic depletion histology further received light chemother2

Carde P. Chemotherapy in the treatment of early stages: Pro. Second International Symposium on Hodgkin's Disease, Cologne, October 3-5, 1991.

apy (vinblastine with or without procarbazine). In patients with favourable histology and therefore no adjuvant chemotherapy there was a somewhat higher (though not statistically significant) incidence of relapse in the no laparotomy arm than in the laparotomy arms. In patients with unfavourable histology (who received adjuvant chemotherapy) the incidence of relapse was much lower. Furthermore, the incidence of relapse was identical in the laparotomy and no laparotomy arm. The conclusion was therefore that laparotomy should only be used for patients with favourable characteristics who would receive radiotherapy alone. Consequently, in the H5 trial of the EORTC laparotomy was performed only in patients with favourable characteristics. Patients with negative laparotomies were randomized to either mantle field irradiation alone or mantle field plus paraaortic irradiation. No significant difference was found in either recurrence free or overall survival. Patients with poor prognostic characteristics or positive laparotomy were randomized to either total (or subtotal) nodal irradiation or combined modality treatment. In these patients recurrence free survival was significantly better in patients treated with combined modality, and the difference in survival was of borderline significance [20]. In the H6 trial patients with favourable prognostic characteristics were randomized between mantle field plus paraaortic field plus spleen irradiation or laparotomy with treatment depending on the findings at laparotomy. The recurrence free survival in the laparotomy staged patients was somewhat higher than in the clinically staged patients, cause specific survival was identical in the two arms, but overall survival was slightly inferior in the laparotomy staged patients due to the laparotomy related deaths [211. Based on these findings laparotomy is no longer used in the EORTC trials. Another advantage of using chemotherapy up front would be that it might enable us to reduce radiation fields and doses, and thus hopefully reduce the incidence of complications, in particular cardiac related morbidity and mortality, gastrointestinal injuries, and second solid tumours [22]. In the EORTC H5 trial it was shown that, as regards survival, the addition of MOPP to mantle field irradiation allowed the deletion of paraaortic and splenic irradiation [20]. In the H6 trial this was taken one step further. Patients with unfavourable characteristics all received chemotherapy and in these patients the subcarinal part of the mediastinal field was deleted [21]. In the ongoing H7 trial this has been taken even further, so that patients receiving chemotherapy only receive involved field radiotherapy. Follow-up of the patients in these trials is still too short for conclusions to be drawn. In the ongoing HD1 trial for the German Hodgkin Study Group patients with unfavourable characteristics are treated with chemotherapy and randomized between extended field irradiation to either 40 Gy or to 20 Gy with additional 20 Gy to bulky sites [23]. Results so far are identical in the two arms.

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randomized trials, published or unpublished, of prophylactic combination chemotherapy in Hodgkin's disease were presented. From each trial data had been requested on the total number of patients randomized to each treatment arm, and the number of these patients who were known to have died. In addition, tabular data were requested on numbers of patients randomized and numbers dying, split by age and stage. Full data were available on 69% of eligible patients, data from published reports on 17%, and no data on 14%. Data on a total of 2,069 patients randomized in trials of adjuvant chemotherapy were analysed. Chemotherapy appeared to produce a proportional reduction in the hazard of death of about 15%, but this reduction was not statistically significant. There was no indication that the effect of adjuvant chemotherapy differed in subgroups defined by age, stage, and B-symptoms. The Copenhagen-Oxford metaanalysis has succeeded in bringing together updated survival data from nearly all trials that have assessed prophylactic chemotherapy in early Hodgkin's disease. It represents the largest amount of properly randomized evidence on Hodgkin's disease treatment ever analysed together. And yet, there are still not enough data to establish definitively whether the small improvement in survival seen in the preliminary analyses is ultimately real or not. The organizers are now trying to increase the statistical power of the analyses by obtaining individual patient data and information on recurrences and causes of death. For the time being, however, the preliminary conclusion is that we still do not definitively know whether or not the addition of prophylactic chemotherapy up front significantly improves survival in early stage Hodgkin's disease treated with irradiation.

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patients in CS II. These patients do not need a laparotomy, but without staging laparotomy a substantial portion will require paraaortic and splenic irradiation if radiation alone is to be used, instead of just a mantle field. Patients with an intermediate risk (20%-40%) of occult abdominal involvement include patients in CS IIA (except young females) and patients in CS IB and KB. Their risk is too high to recommend radiation therapy alone without staging laparotomy, but if the laparotomy is negative chemotherapy can be avoided in the majority of these patients. Studies of PS IA and HA patients treated with mantle and paraaortic irradiation consistenly show 10-year disease free and overall survival greater than 80% [27-29]. Less than 50% of deaths at 15-20 years are from Hodgkin's disease. The only factor predicting for relapse in multivariate analysis is large mediastinal adenopathy. For patients with PS IB and IIB disease treated with mantle and paraaortic irradiation results are also quite good if patients with extensive B-symptoms (both fever and weight loss) are excluded. If these patients are excluded 10-year disease free and overall survival are greater than 70% and 80% respectively [30].

Arguments against the use of chemotherapy in the initial treatment of early stage disease 3

Alternative approaches to mantle and paraaortic irradiation for early stage disease have been tested in several studies. To reduce the size of radiation fields mantle field irradiation alone has been tested in PS IA and IIA patients with favourable prognostic characteristics with results comparable to those obtained with mantle and paraaortic irradiation [5, 31, 32]. To eliminate staging laparotomy mantle field irradiation alone has been employed also in CS I and II patients. Early studies seemed to indicate that this approach yielded an unacceptably low disease free survival [5, 33]. However, in studies restricting patients to CS IA results are somewhat better [31, 33]. It still remains to be determined which patients are suitable for mantle field irradiation alone without staging laparotomy. Recently, trials have been initiated testing lighter chemotherapy in addition to radiotherapy to reduced fields. At Stanford the combination of vinblastine, bleomycin and methotrexate in combination with involved field irradiation is being tested against extended field irradiation in CS IA and IIA patients [7]. Of the three drugs used in this study vinblastine is probably the main active drug, so that this study in effect bears resemblance to the very early EORTC HI study of adjuvant vinblastine [5]. At the M.D. Anderson Hospital in Texas two cycles of MOPP followed by mantle field irradiation for PS I and II patients with unfavourable characteristics has been tested with somewhat uncertain results [34]. The Cancer and Leukemia Group B is currently testing the EVA regimen (etoposide, vinblastine, doxorubicin) in addition to mantle and paraaortic irradiation in early stage patients with unfavourable characteristics.

The goal of using radiotherapy alone in the treatment of early stage Hodgkin's disease is to minimize complications by avoiding chemotherapy and by reducing radiation field sizes and doses as much as possible. The requirement is that a high freedom from relapse rate should be maintained in order to reduce the number of patients requiring retreatment with potentially toxic therapy, not because these patients are not cured at relapse but because it is desirable to avoid the drugs needed to obtain this cure. Thus, the intensity of initial treatment must be balanced with the likelihood of relapse and the need for retreatment. To maintain a high freedom from relapse after radiotherapy alone careful treatment techniques should be used, as defined by the Patterns of Care Study in the U.S.A. [24]. Careful staging including staging laparotomy and thoracic CT-scanning allows appropriate selection of patients for initial chemotherapy. Thoracic CT-scanning also allows shaping of the lung and cardiac blocks more accurately so as not to block Hodgkin's disease. The information obtained from staging laparotomy strongly affects the extent of treatment needed. Most PS III patients require chemotherapy, PS I and II patients can be effectively treated with radiotherapy. Groups of patients with a low risk (less than 10%) of occult abdominal involvement can be delineated [25, 26]. These include female patients in CS IA, male patients in CS IA with lymphocytic predominance histology and/or high neck involvement, and young female •' Mauch P. Chemotherapy in the treatment of early stages: Contra. Second International Symposium on Hodgkin's Disease, Cologne, October 3-5, 1991.

The treatment policies for early stage patients currently used at the Joint Center for Radiation Therapy are as follows. Most patients in PS IA or IIA with nodular sclerosis or lymphocytic predominance histol-

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The use of chemotherapy up front reduces the risk of relapse and thus helps to avoid salvage therapy for relapse in many patients. In this way the psychological stress of experiencing a relapse is also avoided. Long term survival for relapsing patients is not good. For early stage patients in the large International Database on Hodgkin's Disease it is less than 60% after 10 years [1]. Chemotherapy for relapse may often be more intensive and toxic than prophylactic chemotherapy, and hence the latter may be more attractive even though it will have to be administered to all patients, whether they would otherwise have experienced a relapse or not. However, it must be remembered that, as indicated above, no overall survival benefit has yet been definitively documented from the use of chemotherapy up front as opposed to reserving it for relapse treatment only. Newer types of chemotherapy, hopefully more effective and/or less toxic, may conceivably in the future bring about a significant improvement in overall survival if used prophylactically as part of the initial treatment.

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ogy are treated with mantle field irradiation alone. Patients with extensive B-symptoms or large mediastinal adenopathy are not staged with laparotomy and are all treated with combined modality. The intermediate group still remains problematic. With staging laparotomy and mantle and paraaortic irradiation these patients have quite a good disease free survival. However, these patients might benefit from newer approaches with modified chemotherapy and radiotherapy, perhaps combined with a reduction of the role of staging laparotomy. Trials of chemotherapy alone in early stages 4

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Magrini SM. Radiotherapy vs. chemotherapy. Second International Symposium on Hodgkin's Disease, Cologne, October 3-5, 1991. Santarelli MX Chemotherapy vs. combined modality. Second International Symposium on Hodgkin's Disease, Cologne, October 3-5, 1991.

Conclusion

Modern treatment, whether consisting of radiotherapy, combination chemotherapy or combinations of these modalities, can cure the vast majority of patients with early stage Hodgkin's disease. Comparisons of the different treatment approaches in randomized trials have not yet been able to establish a definitive superiority of one approach over the others. This may partly be because, although disease free survival and short-term toxicity can be compared fairly easily, the endpoints that are ultimately decisive, i.e. survival and long-term toxicities such as cardiac sequelae and second tumours, require very large numbers of patients and very long follow-up. Newer treatment approaches are now being introduced worldwide. However, it is important to bear in mind that, just as a moderate improvement in survival requires a large number of patients to be reliably detected, so also a moderate deterioration in treatment results will only be detected in equally large randomized trials. In order not to jeopardize the good results achieved with the standard treatments developed over the last three decades, newer treatment approaches should consequently be tested in large randomized trials and be carefully weighed against current treatment practices before being implemented for general clinical use. References 1. Henry-Amar M, Aeppli D, Anderson J et al. Workshop statistical report. In Somers R, Henry-Amar M, Meerwaldt JK et al. (eds): Treatment strategy in Hodgkin's disease. Proceedings of the Paris International Workshop and Symposium, June 28-30, 1989. Colloque INSERM No. 196. London, Paris: INSERM/John Libbey Eurotext 1990; 169-422. 2. Nissen Nl, Nordentoft AM. Radiotherapy versus combined modality treatment of stage I and II Hodgkin's disease. Cancer Treat Rep 1982; 66: 799-803. 3. Anderson H, Deakin DP, Wagstaff J et al. A randomised study of adjuvant chemotherapy after mantle radiotherapy in supra-

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Two randomized trials have tested chemotherapy versus radiotherapy in early stage disease with conflicting results. The NCI study was initiated in 1978 and a total of 106 patients have so far been randomized [35]. The Italian multicentre study was conducted from 1979 to 1982 and a total of 89 patients were entered [36]. In both studies chemotherapy consisted of MOPP and radiotherapy was extended field irradiation. The conclusion of the NCI study was that response rate was equal in the two treatment arms but that disease free and overall survival was significantly better for the patients treated with chemotherapy. The NCI study has been criticised because it included patients with massive mediastinal involvement or PS IIIA disease, patients who are not suited for treatment with radiotherapy alone |37]. If these patients are excluded from the analyses there is no longer any difference between the two treatment arms. The Italian study, from which updated results were presented at the Cologne Symposium on Hodgkin's Disease, showed quite different results. Complete response rate was poorer in the chemotherapy arm than in the radiotherapy arm (90.9 % vs. 100%). Freedom from progression was not significantly different, though slightly worse in the chemotherapy arm (64% vs. 76% at 9 years). However, patients relapsing after chemotherapy had a significantly poorer survival after relapse than did patients relapsing after radiotherapy (15% vs. 85%). All this resulted in a significantly poorer overall survival of patients treated with chemotherapy (65% vs. 93% at 9 years). Three more patients in the chemotherapy arm died of second cancers (acute myeloid leukemia, colorectal cancer, breast cancer). Compared with the NCI study the chemotherapy treated patients of the Italian study fared considerably worse. This could be explained only by the intrinsic variability in MOPP results, since percent projected drug rates were >90% for all the drugs. Of more interest is the higher

incidence of 'in field' relapses among NCI patients randomised to radiotherapy (7/17, 41.2% vs. 1/12, 8.3%), even though the proportion of irradiated patients with bulky mediastinal masses was higher in the Italian study (8/45, 17.7%, as opposed to 3/51, 5.8%). The GATLA group in Argentina conducted a randomized trial of chemotherapy (CVPP) alone versus combined modality treatment in CS I and II from 1977 to 1986 [38]. A total of 277 patients were entered into the trial, 45% of these were children under 16. Complete remission rate was not significantly different in the two arms. Disease free survival at 8 years was 64% in the combined modality arm and 53% in the chemotherapy arm, which is significantly poorer. The difference was confined to patients with unfavourable characteristics, i.e. age over 45 and/or extensive disease. Overall survival was not significantly different in the two treatment arms.

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Correspondence to: Dr. Lena Specht Department of Oncology Herlev University Hospital DK-2730 Herlev, Copenhagen, Denmark

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