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Adjuvant and neoadjuvant chemotherapy for soft tissue sarcomas: a personal point of view

Abstract

Dr. Gianni Bonadonna is internationally recognized as one of the foremost medical oncologists of the 20th century. He is best known for his pioneering work in the development of adjuvant chemotherapy for breast cancer, but he was also the father of sarcoma chemotherapy. The first investigator to study the new chemotherapeutic agent adriamycin in the late 1960s, he noted activity against sarcomas. This article, focusing on adjuvant chemotherapy, adriamycin, and sarcomas, memorializes his achievements and their progeny.

Tumori 2017; 103(3): 213 - 216

Article Type: REVIEW

DOI:10.5301/tj.5000628

Authors

Robert S. Benjamin

Article History

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: The author has no conflict of interest with this submission.

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Introduction

Dr. Gianni Bonadonna was the father of sarcoma chemotherapy. One of the foremost medical oncologists of the 20th century, he is internationally recognized for his pioneering work in the development of adjuvant chemotherapy for breast cancer (1), but I knew him as the first oncologist to use adriamycin, before it was renamed doxorubicin (2). In 1971 as a Clinical Associate (equivalent to a Fellow) at the Baltimore Cancer Research Center, a branch of the National Cancer Institute, I had been assigned the project of studying the clinical pharmacology of a new drug, adriamycin. Our branch had a focus on the therapy of acute leukemia and had studied daunorubicin, the first anthracycline antibiotic in clinical use and a highly active agent against acute leukemia. My laboratory boss, Dr. Nicholas Bachur, had developed a fluorescent assay for daunorubicin and had studied its clinical pharmacology. He had read some articles from an Italian investigator, Dr. Gianni Bonadonna, about the use of a new anthracycline, adriamycin, that showed clinical activity against a variety of solid tumors (2, 3). Since adriamycin differed from daunorubicin by only a single hydroxyl group, the techniques developed by Dr. Bachur to study daunorubicin could easily be used to study adriamycin, but to study the clinical pharmacology, we needed a protocol to administer the drug. My clinical boss, Dr. Peter Wiernik, a leukemia expert, asked me how many patients the study would require, and how rapidly we would need to enroll them. I said that I did not know for sure and guessed about 15 patients, but that it would take me about a week to study a single patient in order to obtain the samples over 72 hours and take another 2 to 3 days to process them. He said to go ahead with the protocol since we had patients and very little effective therapy, but not to get my hopes up. Adriamycin, after all, “was just a daunorubicin analog, and analogs never work.” Meanwhile, Dr. Bachur told me to make sure to include patients with sarcomas on my protocol because Dr. Bonadonna had reported responses in patients with sarcomas, and he could not recall any drug that worked against sarcomas (3). So I wrote the protocol and started looking for patients to study.

Because I personally administered the drug and was with the patient for the first hour afterwards obtaining blood samples, returning for further samples multiple times over the next 72 hours, I got to see what few oncologists today see, now that we have professional infusion nurses and phlebotomists who spend time with the patient at or around the time of chemotherapy administration. The second patient on my study had a rhabdomyosarcoma with widespread bone metastases. He had been bedridden in the hospital for several weeks with pain poorly controlled with morphine. When I returned to draw my 4-hour sample, he told me he was feeling better, and I remember thinking how powerful the placebo effect could be. After all, I was the first doctor to take a real interest in him, had spent an entire hour with him, and then returned to visit him 2 more times. At the time of my 24-hour sample, he was sitting up on the edge of the bed, and after my 72-hour sample, he walked out of the hospital. Dr. Bonadonna was indeed correct, and thanks to Dr. Bachur’s astute reading of his articles, we had confirmed that adriamycin was indeed active against sarcomas. I reported my observations to Dr. Wiernik, who rapidly changed his mind about analogs and wanted me to expand accrual on the protocol. We accrued 96 patients (4) and reported the activity of adriamycin in 36 patients with sarcomas (5). That first patient got me interested in the treatment of sarcomas, and I continue to learn about these fascinating diseases more than 45 years later.

Early in my career, I attended many meetings about that interesting new drug, adriamycin, and I got to meet Gianni Bonadonna. I was in awe of him. He was a strikingly handsome man, and when he spoke with quiet authority and insight, everyone paid attention. After we had met several times, we developed a friendship, cemented by a mutual love of opera. We went together to La Scala—my first time—to hear Luciano Pavarotti in Un Ballo in Maschera (not his best night, but it was La Scala). Although Dr. Bonadonna never concentrated on the therapy of sarcomas, he was truly the father of sarcoma chemotherapy, and his former fellow, Dr. Paolo Casali, now leads one of the best sarcoma medical oncology programs in the world. Dr. Bonadonna’s work in breast cancer concentrated on adjuvant chemotherapy, so it is fitting to discuss adjuvant chemotherapy for soft tissue sarcomas in the Bonadonna Lecture series.

I shall not provide an exhaustive review of all studies on adjuvant therapy, but rather provide commentary on some of the important publications in the area. Interested readers are referred to the excellent review by Ravi and Patel (6). In 1995, a group of investigators met in Cambridge, England, to review the state of the existing data from existing studies and to initiate a meta-analysis of individual patient data. The studies varied tremendously. They included tumors of all grades, at different locations, with different local therapy. It was clear that in almost half the studies, surgery was inadequate. The only group of studies where there was reasonably uniform and adequate local therapy was the group with primary tumors of the extremities, and several of the investigators at the meeting proposed limiting the meta-analysis to those patients. Others suggested including data from all patients, but performing a separate, prespecified analysis limited to the patients with primary extremity tumors. Those data are confined to a single forest plot in the article (7), but demonstrate clearly that even at that time, adjuvant chemotherapy provided a small but real survival advantage of 7% (hazard ratio 0.8, p = 0.029; Fig. 1). When the data were diluted by the studies with low-grade tumors and/or inadequate surgery, a disease-free survival advantage and local control advantage remained, but the survival advantage of 4% had crossed out of the traditional limits of statistical significance (hazard ratio 0.89, p = 0.12), so what people remember is simply that there was no survival advantage. It is unfortunate that the meta-analysis was not limited to the studies of patients with primary extremity tumors. The main conclusion would have been different, and we could have progressed to studies designed to improve the results rather than prolong the controversy. Contamination of the patient population with those with inadequate local control or those with low-grade tumors diverted attention from the critical question: can adjuvant chemotherapy eliminate micrometastases and thereby help cure patients with high-risk soft tissue sarcomas whose primary tumors have been adequately controlled by local modalities?

Survival of patients with extremity sarcomas with or without adjuvant chemotherapy from the meta-analysis of individual patient data.

The second meta-analysis by Pervaiz and colleagues (8) incorporating newer studies with ifosfamide-containing combinations strengthened the conclusions that should have come from the first with a hazard ratio of 0.77 and p = 0.01 for all studies and a hazard ratio of 0.56 and p = 0.01 for those containing ifosfamide.

The controversy continued, however, because the largest adjuvant study (from the European Organization for Research and Treatment of Cancer) involving 351 patients using 75 mg/m2 of adriamycin on day 1 and 5 g/m2 of ifosfamide as a 24-hour infusion on day 1 had not been published at the time of Pervaiz’s analysis, and that study showed no survival advantage for adjuvant chemotherapy (hazard ratio 0.94, p = 0.72) (9). A number of factors may have contributed to the observed result: only 2/3 of the patients had primary tumors in the extremities, only 2/3 of the patients had adequate surgery, and only 2/3 of the patients had high-grade tumors, the dose of ifosfamide was low, and the schedule of ifosfamide administration was suboptimal. Nonetheless, careful inspection of the survival curves from that study reveals that there was a clear delay in time to recurrence and mortality, even if the disease ultimately recurred and the patients died. Despite only 15 weeks of chemotherapy, the 2-year recurrence-free survival was 6% higher in the treated group, resulting in a similar improvement in 3-year survival. The correct interpretation of the data is not that adjuvant chemotherapy did not improve survival but rather that the chemotherapy employed in that study was inadequate to destroy all remaining tumor cells left behind after local therapy (surgery with or without radiation or isolated limb perfusion) leading to a delay, but not prevention, of ultimate tumor recurrence and death. If the chemotherapy worked partially, there was clearly a need for chemotherapy, so the correct question to ask in subsequent studies is not whether chemotherapy helps but rather which chemotherapy regimen helps the most.

The most interesting studies in this regard come from the Italian Sarcoma Group, carrying on the Bonadonna tradition. Their first adjuvant study limited patient entry to 104 patients with large, deep, high-grade tumors of the extremities or limb girdles after adequate local therapy (10). Patients were randomized to 5 courses of ifosfamide 1.8 g/m2 daily × 5 and epirubicin 60 mg/m2 daily × 2 or no adjuvant therapy. There was clear benefit in both disease-free survival and overall survival. This chemotherapy program became the standard for those participating in the initial protocol. In a retrospective review of the data on an additional 55 patients treated after the close of the protocol, the disease-free survival rates at 2 and 4 years were 73% and 57%, respectively; the corresponding overall survival rates were 91% and 70%, respectively (11).

The Italian Sarcoma Group in collaboration with the Spanish Sarcoma Group performed a study with the same chemotherapy regimen comparing 3 courses of therapy given preoperatively versus 3 courses preoperatively and 2 postoperatively (12). They found no advantage in adding the postoperative therapy, but confirmed the results found in the treatment arm of the initial Italian Sarcoma Group study.

In an attempt to improve on these results, the same group of investigators in collaboration with the French and Polish Sarcoma Groups next randomized patients to their new standard 3-course epirubicin-ifosfamide regimen versus histology-directed chemotherapy. The results are not yet published, but they were presented at the 2016 Annual meeting of the Connective Tissue Oncology Society (13). The experimental treatment was not successful, proving significantly inferior to the standard epirubicin-ifosfamide treatment. An alternative interpretation of the data is that there were statistically significant benefits of adjuvant therapy from the epirubicin-ifosfamide regimen over the histologically directed regimens in terms of disease-free survival and overall survival. I hope that at the time of formal publication of these data the authors do not conclude that histologically directed chemotherapy is ineffective and should not undergo further study. Nothing could be further from the truth. A better interpretation of the data would be that the regimens chosen for the specific sarcoma types were less effective than the broad-spectrum epirubicin-ifosfamide regimen chosen as the control and that further studies to improve chemotherapy for specific histologic subtypes of sarcomas are indicated. For myxoid liposarcoma, trabectedin was as effective as epirubicin-ifosfamide. How about epirubicin-trabectedin or the 3-drug combination for myxoid liposarcoma? Perhaps incorporation of trabectedin into a regimen for leiomyosarcomas or addition of pazopanib to the standard ifosfamide schedule (rather than the 14-day infusion used in the previous study) with or without epirubicin for synovial sarcomas might be better? Perhaps sequential combinations will be needed. Let us work to get better treatments for each sarcoma type and then, once we find truly better regimens, put them to the test.

Further analysis of the results of the preoperative therapy using modern imaging interpretation may identify the patients who showed benefit from preoperative therapy (14). It would be of interest to see if they did better than patients who did not demonstrate response. The neoadjuvant approach permits early confirmation of what remains as the investigator’s best guess rather than the best regimen. If the best guess is clearly wrong, the second best cannot be worse. Despite the fact that the histology-tailored chemotherapy did not improve survival, use of alternative chemotherapy in patients not demonstrating benefit from the epirubicin-ifosfamide regimen might improve their chances. It would be worth testing.

Adjuvant or neoadjuvant chemotherapy is now considered the backbone of therapy for osteosarcoma, but early studies of adjuvant therapy for that disease were criticized as widely as studies for soft tissue sarcomas. It was not until effective combinations were developed that investigators started concentrating on how to improve results rather than prove that patients destined to die of metastatic disease required systemic therapy. The therapy for soft tissue sarcomas has lagged behind that of osteosarcoma, and oncologists are still debating the value of combination chemotherapy over single-agent doxorubicin. It is clear, however, that if you want to make a tumor smaller or stop it from growing, the chances are twice as good using doxorubicin and ifosfamide than doxorubicin alone (15, 16). There is no clear advantage of doxorubicin or epirubicin, so the Italian studies supporting the epirubicin-ifosfamide combination support what we know about doxorubicin-ifosfamide from the metastatic disease setting. Let us not go back to letting patients die of potentially preventable metastatic disease simply because it has not been proven that we know how to do it. The Italian Sarcoma Group studies indicate that we have made a small step forward. Let us build on that rather than taking 2 steps back.

Disclosures

Financial support: No financial support was received for this submission.
Conflict of interest: The author has no conflict of interest with this submission.
References
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Authors

Affiliations

  • Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX - USA

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