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Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna

Abstract

This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin’s disease and diffuse large B cell lymphoma.

In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent.

Tumori 2016; 102(2): 124 - 126

Article Type: REVIEW

DOI:10.5301/tj.5000492

Authors

Vincent T. DeVita, George P. Canellos

Article History

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.

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Introduction

Because of the nature of clinical research, relying as it does on the successful control of so many variables extraneous to the patient, collaboration is the essence of patient-related research. It does not come easily, and investigators often struggle to develop collaborations with colleagues across departments or even in their own departments. Therefore, it is a unique event when a successful collaboration is established between investigators from different nations separated by thousands of miles and different cultures. This was the case with us and Gianni Bonadonna. It began when we were all enthusiastic, young investigators with ambitious goals to control cancer and continued as an enduring friendship in succeeding years through Bonadonna’s heroic struggle with an incapacitating illness. This review tells that story, focusing on the early years and the efforts of the groups concentrating on breast cancer and the lymphomas in the Medicine Branch of the US National Cancer Institute (NCI) in Bethesda, Maryland, and the Istituto Tumori in Milan, Italy.

Breast cancer

Although we had met Gianni Bonadonna previously at cancer meetings, our first long encounter occurred in 1969 when he made a visit to NCI’s Medicine Branch to review our new program, cyclophosphamide, methotrexate, and fluorouracil (CMF) for treating breast cancer (1). Our group had developed the successful mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) program for Hodgkin disease (2) and applied the same principles of a cyclical combination chemotherapy program for breast cancer. It had worked well in patients with advanced breast cancer, producing a then unique 20% complete remission rate. Then as now, the majority of patients with breast cancer presented with what appeared to be localized disease, even though a significant majority would eventually relapse, so a postoperative adjuvant program was sorely needed. Our interest was in applying CMF as an adjuvant to initial surgery to prevent relapse. The surgical breast program at the NCI was very small, with not enough patients to launch an adjuvant chemotherapy program. Inquiries were made to major cancer centers in the United States, but there was no interest and considerable skepticism for using combinations of toxic drugs in patients, some of whom might never relapse. The Chief of the Medicine Branch at the time, Dr. Paul Carbone, made contact with the Director of the Istituto Tumor, Professor Umberto Veronesi, a renowned breast surgeon, to explore the potential of collaboration. He sent Gianni Bonadonna to Bethesda to investigate the possibility of a joint effort. Gianni spent a week with us, carefully reviewing the chart of each patient whom we had treated with CMF. During that period, we had the opportunity to discuss our joint goals, and a bond developed between kindred spirits. Bonadonna convinced Professor Veronesi to take on a large randomized adjuvant trial of CMF as a single-institution effort. Many barriers had to be overcome. The Italian government was reluctant to provide the necessary resources, so an NCI contract did, and the cultural difference between the United States and Italy over the extent of the informed consent needed to be accommodated. Also, we had many discussions about drug doses of CMF. In the end, Bonadonna insisted on slightly reduced doses for the trial as he feared excessive toxicity, especially in older Italian women. The trial results were published by The New England Journal of Medicine in 1976, showing that postoperative combination chemotherapy could effectively and safely be given to breast cancer patients (3). The CMF study was the first of its kind to show a reduction in mortality as a result of postoperative chemotherapy. The dose issue remained to be solved; in a manner typical of his attention to detail, Bonadonna would later show, in a controlled trial, that reducing doses indeed would have a deleterious effect on outcome, especially in older patients (4).

He also explored the question of duration of therapy in another randomized trial that showed there was no additional benefit in treating patients with CMF for 12 months compared to 6 months (5). These brilliant CMF trials vaulted Gianni Bonadonna into international visibility and also set the precedent for the use of adjuvant chemotherapy for breast cancer throughout the world. While CMF is no longer the adjuvant program of choice in breast cancer, virtually all current programs are built on the principles established in the United States and Milan trials. In the United States alone, mortality from breast cancer has declined by 25%, and most of the decline is due to the successful application of adjuvant chemotherapy.

Hodgkin disease

The NCI contract with the Istituto Tumori also established and funded a clinical trials office, which provided Bonadonna with a powerful research tool to explore other important questions in clinical research of joint interest to both institutions. The NCI MOPP program proved that a cure of an advanced solid tumor of a major organ system in adults was possible with combination chemotherapy, a major conceptual advance (2). While the NCI was developing MOPP, Bonadonna was testing the then-new anticancer drug adriamycin. He was one of the first to show its activity in humans (6). He had also tested the use of the MOPP program in Italy with favorable results and set about to develop a combination of drugs that would be non-cross-resistant to MOPP to use in MOPP failures using the same principles used to structure the MOPP program. This resulted in the development of the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) program (7). He then began another series of brilliant clinical trials in lymphomas focusing initially on Hodgkin disease. This included a study of ABVD in MOPP failures, showing ABVD was not cross-resistant to MOPP (8); a comparison of ABVD to MOPP, showing it was at least as effective as MOPP and had a more acceptable toxicity profile (9); and studies comparing ABVD to various alternating drug combinations (10). The end result was that ABVD prevailed and became the mainstay of the treatment of Hodgkin disease of all stages. These results were confirmed in a large study by the Cancer and Leukemia Cooperative Group study (11) that showed equivalent cure rates for both MOPP and ABVD. A study at the NCI comparing MOPP treatment to total nodal radiation in patients with early-stage disease showed MOPP to be the superior treatment and launched the study of combination chemotherapy alone or in combination with radiation therapy for patients with localized disease (12, 13). The studies at the US NCI and the Istituto Tumori radically altered the outcome of patients with Hodgkin disease worldwide. Now almost all patients with Hodgkin disease are treated with combination chemotherapy with or without radiotherapy and upwards of 85% of all patients with the disease are curable. In the United States, this has resulted in a decline in mortality from Hodgkin disease by over 80%.

Non-Hodgkin lymphoma

In the late 1960s and early 1970s, the NCI Medicine Branch developed a modification of the MOPP regimen by substituting cyclophosphamide for nitrogen mustard, the so-called C-MOPP program. In this trial of 27 patients with advanced disease, 11 (41%) patients achieved a complete remission (14). Of these 11, 6 were stage IVB, 4 were stage IIIB, and 1 was stage IIB. That only 1 stage IVB patient relapsed with 10 of the 11 complete responders remaining in remission was a unique observation at the time. A critical observation made from this trial was that if a patient remained in complete remission for 2 years off therapy, he or she was likely cured of this otherwise rapidly growing tumor. Figure 1 shows an extended survival curve for this group that illustrates this point. This study established that diffuse large B-cell lymphoma was another curable disease and this was stated in the title of the article we published.

Life table analysis of patients with diffuse large B-cell lymphoma treated with C-MOPP (14).

Dr. Bonadonna’s unit in Milan was also concerned with combination chemotherapy for non-Hodgkin lymphoma. They piloted a regimen known as nitrogen mustard, adriamycin, bleomycin, vincristine, and prednisone (MABOP). To improve results, they tested using 2 non-cross-resistant regimens: cyclophosphamide, vincristine, and prednisone (CVP), a regimen also developed by the NCI Medicine Branch team; and adriamycin, bleomycin, and prednisone (ABP), a protocol developed by Bonadonna’s group. The program was active in inducing complete remissions, as was MABOP, but neither could be documented to have resulted in a cure of large cell lymphoma at that time (15). The Milan group also compared ABP to the more established treatment of CVP in patients with the more indolent forms of non-Hodgkin lymphoma. They showed that ABP had comparable activity that could be used as the basis of future regimens. The new agents at the time, such as AMSA and mitoxantrone, were also studied by Bonadonna’s group (16, 17), as well as the early successful application of human granulocyte-macrophage colony-stimulating factor to reduce the myelotoxicity of high-dose chemotherapy with cyclophosphamide (18). His team employed combined modality therapy with chemotherapy and radiation for locoregional aggressive lymphoma with a 5-year survival of 83%. That approach was further refined in primary gastrointestinal lymphoma following surgery with a 10-year survival and freedom from progression of 85% (19). Bonadonna’s team members were early contributors to the role of intensive therapy for poor prognosis non-Hodgkin lymphomas. They showed that more intensive chemotherapy with autologous stem cell support was superior to a conventional doses regimen used at the time, MACOP-B. Superior event-free survival was achieved with an advantage in overall survival as well (20).

The total body of work on the chemotherapy of solid tumors of the group at the Istituto Tumori, under the leadership of Gianni Bonadonna, was impressive and set the tone for clinical investigations in cancer throughout Europe. Many European patients owe their lives to his insightful approach to research involving patients.

Conclusion

It was clear to us in North America that Bonadonna had assembled a group in Milan who were innovative. He was a leader highly respected by all for his contributions to lymphoma and breast cancer treatment. We considered him a trusted and respected colleague in the fight against cancer. He will be forever remembered as one of the pioneers in medical oncology. We were honored to know him as such.

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.
References
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Authors

Affiliations

  • Yale Cancer Center, Yale University School of Medicine, New Haven, CT - USA
  • Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA - USA

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