How a Bold Thinker Helped Introduce Chemotherapy Combinations to Cancer Therapy

OncologyLive, December 2014, Volume 15, Issue 12

When Vincent T. DeVita Jr, MD, began testing a cocktail of four chemotherapies against advanced Hodgkin disease back in 1964, the disease was uniformly fatal.

Vincent T. DeVita Jr, MD

When Vincent T. DeVita Jr, MD, began testing a cocktail of four chemotherapies against advanced Hodgkin disease back in 1964, the disease was uniformly fatal. Many patients were desperate enough to try anything, even a combination of cell-killing poisons that guaranteed them nothing except excruciating pain.

Their gamble paid off with an unimaginable breakthrough, one that DeVita and his colleagues first reported in 1967: The so-called “MOPP” combination (mechlorethamine, Oncovin, procarbazine, and prednisone) produced complete remissions in 80% of patients.

Had DeVita retired the day after he announced those results, he’d still rank among history’s top oncologists, but the 32-year-old doctor was just getting started. Over the next five decades, he has continued to distinguish himself as an innovator with his contributions to cancer research, including developing a treatment protocol that is still used in breast cancer, publishing more than 400 scientific papers, and running the National Cancer Institute (NCI) for nearly 10 years.

Starting on the Research Path

DeVita stumbled into cancer research by accident. “I actually thought I would ultimately go into [private clinical] practice. But then once you’re involved in a major discovery, you’re hooked! From that point on, I was never even tempted to go into practice,” he said.

Born in the Bronx and raised largely in Yonkers, New York, DeVita stood out as a fast-talking Yankee at The College of William and Mary in Virginia, which was still a school with a very Southern culture when he graduated in 1957 with a degree in chemistry. He married shortly thereafter and moved on to medical school at George Washington University in Washington, DC, in 1957.

DeVita conducted some cardiology research during his time there and managed to get several of his studies published. So, when he decided to continue his studies with a fellowship at the National Institutes of Health (NIH), he expected that any position he landed would be in cardiology. He ended up, instead, at the NCI in 1961, just as research into combination chemotherapy was taking off.

More than a decade had passed since Sidney Farber, MD, first demonstrated that a folic acid antagonist could induce remissions in childhood leukemia. Euphoria about chemotherapy’s promise had been replaced with dire pessimism as each new chemical agent to emerge from the labs failed to produce anything more than temporary remissions.

MOPP’s Difficult Beginnings— and Ultimate Success

By that point, DeVita said, “Nobody felt you could kill cancer with drugs”—nobody except DeVita’s new colleagues at NCI, who believed that chemotherapies that failed as individual treatments just might cure cancer when used together.It is difficult to imagine, now that combination therapy is a cornerstone of cancer treatment, just how controversial this idea was at the time. Nearly the entire medical establishment viewed the “fathers of combination therapy” not only as idiots, but also, thanks to the terrible side effects of their experiments, as sadists to boot. Even colleagues within NCI accused the most aggressive experimenters of running “a butcher’s shop” that performed “cruel and insane” work that should be forbidden outright.

DeVita’s experimental MOPP regimen produced side effects that were extreme even by those standards.

Nausea struck patients with indescribable intensity, while the toxins eradicated their immune systems and made any malady a life-threatening condition.

Among those who survived, most of the men and some of the women were rendered permanently sterile. Some escaped Hodgkin disease only to succumb, about a decade later, to leukemia induced by their treatment.

Nevertheless, DeVita and his colleagues knew almost instantly that they had succeeded beyond anyone’s wildest dreams. Thirty-six of their first 43 patients achieved complete remissions within 6 months of treatment.

On the Fast Track at NCI

The only problem was the name of the new regimen. DeVita called it “Combination 2” until his boss, Emil Frei, III, MD, suggested something catchier. “They’d put together VAMP and BIKE, and because these acronyms were quick, people could remember them,” DeVita said, “But I called it ‘Combination 2.’ And so Frei said, ‘Right. It’s MOPP.’ And it’s been forever MOPP.”DeVita’s early success at NCI led to rapid promotion. He was appointed head of NCI’s Solid Tumor Service in 1968, chief of its Medicine Branch in 1971, and clinical director for the entire institute in 1975. Each position brought more administrative responsibility, but DeVita managed to find time for prodigious amounts of research throughout those years.

Most important among that research was the work, conducted with George P. Canellos, MD, which led to the development of the combination chemotherapy regimen CMF. A pair of programs were designed and tested at the NCI’s Clinical Center. The first used L-phenylalanine mustard (L-PAM) alone. The second used the CMF program, a combination of cyclophosphamide, methotrexate, and fluorouracil. Both programs demonstrated activity in patients with metastatic cancer, but the results with CMF were more impressive.

Canellos and DeVita published results in 1974 that showed the overall response rate was over 50%, and about 20% of patients actually achieved complete remission.

As this research was under way, DeVita and his NCI colleagues were working to launch studies of L-PAM and CMF as an adjuvant treatment for earlier-stage breast cancer, but they struggled to find surgeons willing to subject patients with relatively good prospects to harsh chemotherapy.

Eventually, they contacted Gianni Bonadonna, MD, of the Istituto Nazionale dei Tumori, in Milan, Italy.

Bonadonna came to the NIH Clinical Center to review the results of the CMF protocol, which had not yet been published, and agreed to conduct a randomized, controlled trial of a slightly dose-reduced version of CMF versus no therapy.

Personal Tragedy

The first, very positive results were published in The New England Journal of Medicine in 1976, and set off a flurry of research into the use of combination chemotherapy as a neoadjuvant treatment.These triumphs in the laboratory came at a time when DeVita and his family were suffering personal tragedy. “My son, in 1972, was diagnosed with aplastic anemia.

I brought him in to see Dr Ronald Yankee, and the diagnosis was made, and Yankee put him in a laminar air flow room, which he never left. He lived in the laminar air flow room for about eight years.”

For all those years, DeVita spent several hours a day, nearly every day, talking to Ted, the son who soon became a counselor to the father. It was Ted who advised his dad to accept a presidential appointment from Jimmy Carter and take charge of the NCI, with its staff of 2000 people and its annual budget of $1 billion. A few months later, in early 1980, Ted died of complications resulting from repeated blood transfusions. Vincent DeVita was 45.

Cancer Research Faces a Disillusioned Public

His nine-year tenure at the head of the NCI began at a time when the general public had grown disillusioned with cancer researchers. A decade had passed since President Nixon had declared the “War on Cancer,” and despite some real gains, cancer appeared in little danger of unconditional defeat.

Even DeVita appeared disillusioned with cancer research. In a 1981 interview with People magazine, he sympathized with critics who called the NCI too conservative and questioned whether the NCI he ran would be courageous enough to fund the MOPP experiments he had conducted 15 years before.

Nevertheless, he managed to win wide support for his work as the organization’s head. DeVita was one of very few Carter appointees in any area of the federal government to keep his job when Ronald Reagan became president.

He also proved adroit at getting a president who had promised domestic spending cuts to keep increasing funds for cancer research.

Continued Involvement

Eventually, DeVita grew weary of the political and bureaucratic demands of running the NCI, so he left for Memorial Sloan Kettering Cancer Center in 1989. After another five years, he moved on to Yale University, where he has remained in various capacities ever since.In recent years, DeVita’s research has been focused on evaluating potential molecular mechanisms of physiologic drug resistance in cancer. How, he wants to know, can cancer cells potentially manipulate molecular pathways to circumvent drugs? Another area of interest is identifying appropriate molecular targets for combination, targeted treatment.

“For the true potential of a predictive marker to be realized, the underlying pharmacokinetic parameters of the drug need to be well defined,” he said. Outside of the lab, DeVita has served as both the volunteer president of the American Cancer Society and a member of its board of directors. He wrote the blog “DeVita on Cancer,” posting his thoughts on current cancer news as well as on the history of the “War on Cancer.”

He has, of course, won many awards and accolades for his work over the past five decades, but says he owes much of his success to the very high quality of his colleagues.

“In research, it can’t be done alone,” DeVita said. “It takes immensely talented researchers and a dedicated staff of professionals to make innovative scientific discoveries that can positively impact the lives of cancer patients.”

DeVita’s Impact “Immeasurable”

Dan L. Longo, MD

Professor, Medicine

Harvard Medical School

Brigham and Women’s Hospital

Boston, MA

“Precious few people have developed curative therapy for incurable malignancies. Vincent DeVita, MD, has done this at least twice, devising a combination chemotherapy regimen that took advanced Hodgkin lymphoma from uniformly fatal to cured in over half the patients and another combination regimen that cured nearly half of patients with advanced diffuse large B-cell lymphoma.

“He also pioneered adjuvant combination chemotherapy for women with breast cancer that led to lower rates of relapse and improved survival. The demonstration that combination chemotherapy could cure a solid tumor was a critically important proof of principle that led to the development of therapies for a large number of cancers and attracted many physicians to the nascent field of medical oncology.

“It is difficult to overestimate the spirit of innovation, the creativity, and the depth of courage and strength it took to combine toxic agents into a treatment program that patients could tolerate and was effective. And he did this at a time when no precedent suggested that the goal was achievable.”

Joshua Brody, MD

Assistant Professor

Medicine, Hematology, and Medical Oncology

Mount Sinai Hospital

New York, NY

“Dr DeVita’s impact is tremendous, long-reaching, and so massive, that I’d say it’s almost immeasurable. He fathered multiple concepts—for example, the therapeutic window where agents that can be poisonous to healthy cells could be much more toxic to tumor cells, and that we could target that therapeutic window. Importantly, he promoted the idea of combining multiple chemotherapy agents that had nonoverlapping toxicities, so that clinicians could target the tumor much more effectively and help patients avoid the toxicities. We have converted some cancer types that were, at one time, absolutely incurable to potentially curable because of those concepts and because of Dr DeVita’s work.

“Dr DeVita’s work emphasized empirical work and that has influenced my own research. We have many scientists working in the lab curing cancer in mice and we say in oncology that it’s a good time to be a mouse with cancer, because mice with cancer are doing well. We need that basic science but we also need to bring it to patients. And Dr DeVita is a role model of persisting in real translational work.

“By honoring Dr DeVita, it says to up-and-coming clinicians and scientists that persistence leads to rewards. I think there’s a trend that many aspiring clinicians, investigators, and scientists may begin in academia, but eventually move toward industry—and that trend leads to many beneficial results. But a commitment to academics has a unique set of rewards that cannot be achieved anywhere else.”

DR DEVITA’S SELECTED PAPERS

  • DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014. In press.
  • Canellos GP, Rosenberg SA, Friedberg JW, Lister TA, DeVita VT. Treatment of Hodgkin lymphoma: a 50-year perspective. J Clin Oncol. 2014;32(3):163-168.
  • Chu E, DeVita VT Jr, eds. Physicians’ Cancer Chemotherapy Drug Manual 2014 [Jones and Bartlett Series in Oncology]. Burlington, MA: Jones & Bartlett Learning; 2014.
  • Longo DL, Glatstein E, Duffey PL, et al. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin’s disease. J Clin Oncol. 1997;15(11):3338-3346.
  • Longo DL, Russo A, Duffey PL, et al. Treatment of advanced-stage massive mediastinal Hodgkin’s disease: the case for combined modality treatment. J Clin Oncol. 1991;9(2):227-235.
  • Longo DL, Duffey PL, DeVita VT Jr, et al. The calculation of actual or received dose intensity: a comparison of published methods. J Clin Oncol. 1991;9(11):2042-2051.
  • Bakemeier RF, Anderson JR, Costello W, et al. BCVPP chemotherapy for advanced Hodgkin’s disease: evidence for greater duration of complete remission, greater survival, and less toxicity than with a MOPP regimen. Results of the Eastern Cooperative Oncology Group study. Ann Intern Med. 1984;101(4):447-456.
  • DeVita VT Jr. The James Ewing lecture. The relationship between tumor mass and resistance to chemotherapy. Implications for surgical adjuvant treatment of cancer. Cancer. 1983;51(7)1209-1220.
  • Longo DL, Young RC, DeVita VT Jr. Chemotherapy for Hodgkin’s disease: the remaining challenges. Cancer Treat Rep.1982;66(4):925-936.
  • Lewis BJ, DeVita VT Jr. Combination chemotherapy of acute leukemia and lymphoma. Pharmacol Ther. 1979;7(1):91-121.
  • Schein PS, DeVita VT Jr, Hubbard S, et al. Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma. Ann Intern Med. 1976;85(4):417-422.
  • DeVita VT Jr, Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med. 1970;73(6):881-895.