Author:

Silvio Monfardini

Abstract

In the 1970s and 1980s the introduction of combination chemotherapy regimens greatly improved the cure rates for patients with Hodgkin’s disease. One of these first regimens was the ABVD combination (adriamycin, bleomycin, vinblastine and dacarbazine). This regimen was developed in 1973 by Gianni Bonadonna, Silvio Monfardini and Mario De Lena at the Medical Oncology Unit of the Istituto Nazionale Tumori of Milan, in the attempt to salvage patients with progression of the disease after the MOPP combination (mechloretamine, oncovin, prednisone and procarbazine) designed and developed by Vincent De Vita in the USA. In the previous years, before the combination chemotherapy modality had been developed, this Group, using single sequential agents in patients with advanced Hodgkin’s disease or in progression after radiotherapy, had already positively tested adriamycin [articolo da pubblicare] and bleomycin. The choice of an intermittent chemotherapy regimen including drugs non cross-resistant with those included in MOPP given in combination (adriamycin, bleomycin, vinblastine and dacarbazine). This regimen, called ABVD, provided remarkable results, inducing a high rate of complete remissions, comparable to those obtained with MOPP. ABVD could then represent an useful alternative to MOPP in patient resistant to this combination. The long term results obtained by the Milan Group with ABVD alternated to MOPP in stage IV Hodgkin's disease confirmed the superiority of alternating chemotherapy compared with MOPP alone. ABVD is still used as a standard therapy for Hodgkin’ disease.

Introduction

Up to the the late 50s a diagnosis of Hodgkin's disease, well known now also to the public as a malignancy of the lymph nodes, would have been a death sentence. Since the 30s in France radiotherapy had been recommended for palliation (Chevalier and Bernard, 1932). But only in the 1960s and 1970s, precise radiation therapy techniques, such as involved-field radiation therapy and extended-field radiation therapy, led to improved outcomes for patients with early-stage Hodgkin disease. In the 1970s and 1980s the introduction of drugs singularly active but used in combination (combination chemotherapy regimens) greatly improved the cure rates for patients with Hodgkin’s disease. One of these first regimens was the ABVD combination (Adriamycin [articolo da pubblicare], bleomycin, vinblastine and dacarbazine). The birth of this regimen was originated in June 1973 by a discussion among Gianni Bonadonna, Silvio Monfardini and Mario De Lena at the Medical Oncology Unit of the Istituto Nazionale Tumori of Milan (Bonadonna, 1975). The first page of the original protocol is attached.

Three years before, in December1970, Vincent De Vita, Arthur Serpick and Paul Carbone (De Vita, 1970) in the USA with mechloretamine, oncovin, prednisone and procarbazine in combination (MOPP) had been for the first time showing in patients with Hodgkin’s disease the superiority of this regimen to that previously reported with the use of single drugs. This new golden standard combination was then used also at Istituto Nazionale Tumori of Milan at the beginning of the seventies of the past century to treat patients with advanced Hodgkin’s Disease.

The new combination

The scenario of treatment of Hodgkin’s disease had been changing with the passage from single agents administered sequentially to combination chemotherapy. At the Istituto Nazionale Tumori of Milan in the previous years, when the progression of the disease occurred after the initial treatment with mechloretamine, this drug was interrupted and vinblastine was administered. When a further progression after vinblastine took place, this drug was stopped and procarbazine was used. With the advent of adriamycin, further favourable results at the Istituto Nazionale Tumori of Milan had been achieved patients in patients with advanced Hodgkin’s disease or in progression after radiotherapy (Monfardini, 1973). This increase of the available armamentarium to treat advanced Hodgkin’s disease opened to the Group the perspective of thinking to combinations possibly different from the classical MOPP.

The way of developing new combinations went in a different way in England. There in those years, in the attempt to attenuate the acute toxicity of MOPP, the tendency was that of testing variants of MOPP, as MVPP (mechlorethamine, vinblastine, procarbazine, and prednisone), replacing vincristine with vinblastine to reduce neurological toxicity (Harding, 1991) and LOPP (chlorambucil, vincristine, procarbazine and prednisone), with chlorambucil replacing mechloretamine to reduce nausea/vomiting, myelosuppression, and phlebitis ( Hancock,1991).

The first idea of the Italian Group, rather than trying to reduce the acute toxicity of MOPP as in England, was that of thinking to a markedly different combination in order to achieve equal or superior results to those provided by MOPP. In a 5 drug combination, adriamycin and bleomycin were added to the same drugs of MOPP with the only omission of procarbazine, since it seemed the most promising choice. The new combination was called MABOP (mechloretamine, adriamycin oncovin, bleomycin and prednisone). MABOP provided in fact positive results (complete remission in over 60% of cases (De Lena, 1972). However after the early direct observations by this Group after the MOPP and MABOP treatments of the first cases of secondary tumors, the Group became progressively worried of the carcinogenic potential of the mechloretamine included in the MOPP as well as in the MABOP combinations. Then at the Istituto Nazionale Tumori of Milan after the MABOP experience the second subsequent idea of this Group was that of trying of achieving the same, if not better results, using agents different from those included in the MOPP regimen. The goal being that of increasing the available armamentarium with a combination to solve the problem on how to treat patients not responding or in progression after the MOPP combination, with the advantage of being potentially less carcinogenic. The Author recalls vividly in the Dr Bonadonna’s study, full of the smoke of his cigarettes, the debate on how to develop a new combination for Hodgkin’s disease with adriamycin and bleomycin and other drugs different from those of the MOPP combination.

The discussion ended up with the choice of 4 drugs: adriamycin, bleomycin, vinblastine and dacarbazine (ABVD), all with a mechanism of action different from those of the MOPP regimen. As in the MOPP, this new combination was administered as an intermittent chemotherapy.

ABVD provided remarkable results, inducing a high rate of complete remissions. In the first trial complete remission occurred in 76% of patients treated with MOPP and in 75% of those given ABVD, with no difference between the two regimens as far as stage (IIIB-IIIS and IV). Histologic type, and prior irradiation were concerned (Bonadonna,1973). After the crossover (ABVD administered after MOPP or viceversa for progressive disease or for relapse after initial remission, no cross-resistance between MOPP and ABVD was observed. It was then shown that ABVD could represent an useful alternative to MOPP to be used in MOPP failures (Bonadonna,1973), taking also in consideration that the toxic manifestations after ABVD were in general well tolerated and reversible.

The next step of the same Group, in order to increase the percentage of complete remissions, was to use ABVD in sequential combination with MOPP (ABVD alternated to MOPP). The long-term results of the subsequent studies, comparing MOPP with the administration of MOPP monthly alternated with the non-cross-resistant ABVD regimen, confirmed the superiority of ABVD alternated to MOPP to MOPP alone in terms of freedom from progression, total survival and survival of complete responders (Bonadonna, 1986).

It is now well known that one of the most serious complications of successful chemotherapy treatments for Hodgkin's disease can be an increased incidence of acute non-lymphoblastic leukemia (ANLL) and other malignancies. A retrospective analysis carried out on over 1000 consecutive patients with Hodgkin's disease admitted to the Istituto Nazionale Tumori of Milan between 1965 and 1978 and treated with radiotherapy (RT), chemotherapy or both modalities, revealed that within 10 years from initial therapy, no second malignancies were observed in patients given ABVD with or without RT (Valagussa,1982). With the MOPP-modified regimens developed in England, while acute toxicity was attenuated, the risk of long-term toxicity, in particular secondary leukemia, was not reduced, the long-term results on the outcome of patients being superimposable to those of patients treated with the original MOPP regimen (Viviani,1996).

Conclusions

No difference in the therapeutic results was shown between MOPP and ABVD in patients with advanced Hodkin’s disease. Contrarily to MOPP, the ABVD administration has not been followed by acute ANLL nor by solid tumors. By delivering MOPP alternate to ABVD, it was possible to cure approximately 70% of patients with advanced Hodgkin's disease. ABVD is still used as a standard therapy for Hodgkin’ disease.

References

Bonadonna G., Zucali R., Monfardini S., De Lena M. & Uslenghi C.(1973). Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer, 36(1 ), 252-259.

Bonadonna G., Valagussa P. & Santoro A.( 1986). Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin's disease: A report of 8-year results. Annals of Internal Medicine, 104( 6), 739-746.

Chevalier P., Bernard J (1932). La Maladie de Hodgkin (Lymphogranulomatose maligne). Paris. Mason et Cie.

De Lena M., Monfardini S., Beretta G., Fossati-Bellani F & Bonadonna G. (1972 ). Clinical trials with intensive chemotherapy and Radiotherapy in Hodgkin’s disease. Presented at International Symposium on Hodgkin’s disease. Stanford University School of Medicine, Stanford. Calif. pp 403-420.

De Vita V.T., Jr, Serpick A.A., Carbone P.P. (1970). Combination chemotherapy in the treatment of advanced Hodgkin's disease. Annals of Internal Medicine 73(6): 881–895.

Hancock B.W., Vaughan Hudson G., Vaughan Hudson B., Haybittle J. L. , Bennett M .H., MacLennan K. A., Jelliffe A.M. (1991) 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. British Journal of Cancer. 63 (4): 579-582.

Harding M.J., McNulty L.J., Paul J., Lee F & Soukop M. (1991). Mechlorethamine, vinblastine, procarbazine and prednisone (MVPP) for advanced Hodgkin’s disease. European Journal of Cancer 27(8).1002-1006.

Monfardini, S., Tancini G., Gasparini, M. & Bonadonna G. (1973). Response and Survival in Hodgkin's disease after Sequential Chemotheraphy Employing a Single Agent. Tumori 59 (1) 45-56.

Viviani S., Bonadonna G., Santoro A., Bonfante V., Zanini M., Devizzi L., Soncini F. & Valagussa P., (1996), Alternating Versus Hybrid MOPP and ABVD Combinations in Advanced Hodgkin's Disease:Ten-Year Results. Journal of Clinical Oncology 14( 5 ), 1421-1430.

Valagussa P., Santoro A., Fossati Bellani F., Franchi F., Banfi, A. & Bonadonna, G. (1982). Absence of treatment-induced second neoplasms after ABVD in Hodgkin's disease, Blood 59(3): 488-94.