How Einhorn Helped Turn a Deadly Cancer Into a Curable Disease

The “Giants of Cancer Care” awards program, which the Intellisphere® Oncology Specialty Group launched last year, honors oncology specialists whose work has made a significant impact on the lives of patients with cancer. Lawrence H. Einhorn, MD, was recognized for developing an innovative treatment for testicular cancer that has dramatically improved outcomes for men diagnosed with the disease.

It was a once-in-a-career achievement, the medical equivalent of a walk on the moon.

By adding a single agent to a fledgling treatment regimen, Lawrence H. Einhorn, MD, transformed testicular cancer from a methodical killer of young men into a highly curable condition for many patients, including famed cyclist Lance Armstrong, whom Einhorn treated.

The medical oncologist had been on the faculty at Indiana University (IU) for only a year when he read about a promising early trial of cisplatin for the treatment of testicular cancer. He thought it would make sense to add the metal to a regimen that had also demonstrated some success in treating the disease: bleomycin and vinblastine.

“We did a phase II study in 1974, when the cure rate for metastatic testicular cancer in patients in their 20s and 30s was 5% to 10%,” recalled Einhorn, now 71. “In my youthful exuberance, I was hoping the cure rate would go to 15% or 20%, but over 70% of study participants achieved complete remissions, all but 10% of them lasting.

It’s not often that the FDA will approve a drug based on a nonrandomized, single-institution study. In this case, the results were so profound that it was hard not to be solidly convinced.”

In the 40 years since, Einhorn, now a distinguished professor and Livestrong Foundation Professor of Oncology at the IU School of Medicine, has driven other major advances in the treatment of testicular cancer, coming up with a more effective and less toxic standard regimen and revealing important principles that are being applied to the treatment of other cancer types. At the same time, he has helped develop new treatment strategies for small cell lung cancer.

A Life-Changing Discovery

Einhorn’s goal upon arriving at IU was to study cancers that were already somewhat responsive to chemotherapy, so that small changes in treatment might lead to big improvements in outcome.

In addition to small cell lung cancer, he focused on testicular cancer, initially using the regimen of doxorubicin, bleomycin, and vinblastine that had been developed for other applications at The University of Texas MD Anderson Cancer Center in Houston, where he had recently completed a fellowship.

Although the combination was useful, Einhorn was looking for something still more effective when, in 1974, he learned of a phase I trial of single-agent cisplatin that had sparked brief remissions in patients with testicular cancer who had previously been treated with chemotherapy. He thought the drug would work well with bleomycin and vinblastine, a pairing that was also developed at MD Anderson, in this case specifically for patients with testicular cancer.

“In 1974 or 2013, the principles of putting drugs together are the same,” Einhorn said. “The drugs in the recipe all should have single-agent activity against cancer, different mechanisms, and different types of side effects. You need evidence of a synergistic effect that can be demonstrated in the lab, as was the case with vinblastine and bleomycin, and later with platinum and other drugs.”

At the time, cisplatin was being used in cancers with no standard therapies, after patients had failed other regimens; however, it caused nausea, vomiting, numbness and tingling in the legs, kidney problems, and ringing in the ears before it could do much to fight disease.

Einhorn “figured out how to get around that” by hydrating patients with IV fluids before and during treatment, preventing accumulation of platinum in the kidneys. He also collaborated with pharmaceutical companies to study drugs that could work as antiemetics, including the first-in-class 5HT3 receptor antagonist ondansetron.

Those work-arounds, and cisplatin’s success in treating testicular cancer, saved the heavy metal from extinction as a medical treatment, Einhorn said. “Here we are 40 years later, and platinum is used in first-line chemotherapy for 10 different diseases,” he said. “It’s used more widely in more diseases than any single cancer drug, yet it almost never made it out of the gate.” Einhorn’s trifecta with the regimen is a reminder, he said, that other landmark treatments may be waiting in the wings as investigators research new drugs, such as molecularly targeted agents, to treat cancer.

“I wish that we had a drug like platinum in the other diseases I treat,” he said, “but at least it shows you what is possible, and underscores the urgency of doing clinical trials, because if we’re not looking at new drugs and new studies in other cancers, we’re always going to be at the status quo.”

Chipping Away at Testicular Cancer

Once the “Einhorn regimen” was standard, Einhorn trained translational researchers to help him refine therapy for testicular cancer. He also founded the Hoosier Oncology Group, a consortium of Midwestern oncologists committed to collaborating on studies.

With a strong team behind him, Einhorn led trials of treatments for testicular cancer.

In a phase III study from 1976 to 1978, Einhorn and colleagues demonstrated that the dosage of vinblastine routinely given to patients with testicular cancer could be lowered to reduce the incidence of low white blood cell count and neuropathy, with no reduction in the regimen’s cure rate.

From 1978 to 1981, the group “challenged a basic dogma of oncology— that we had to give a long duration of therapy,” Einhorn said. “Earlier studies gave vinblastine for two years of chemotherapy, even though patients progressed way before the two years were up. We did a phase III randomized trial in which patients in the control arm got two years of chemotherapy versus stopping vinblastine after 12 weeks in the experimental arm, and there was no difference in the cure rate.”

But what about patients who were resistant to, or who recurred on, the Einhorn regimen? Einhorn and his colleagues tested a therapy that combined just platinum and etoposide, and 25% of the patients studied were cured. “It was the first time an adult tumor had been cured with a second- line therapy,” Einhorn said.

From 1981 to 1984, the team followed up with a study substituting etoposide for vinblastine in the standard treatment regimen. The study made the Einhorn regimen “a historical footnote,” he recalled, “because we showed we had fewer side effects with etoposide and a higher cure rate.”

Then, an investigation considered shortening the duration of the new standard therapy. “We gave patients three courses of bleomycin plus etoposide plus platinum over 9 weeks versus four courses over 12 weeks, with the same cure rate,” Einhorn said. “Platinum has cumulative side effects, so this was eliminating the most toxic course, the fourth one. Now, the majority of patients can be cured with just nine weeks of chemotherapy.”

For patients who relapsed on the new standard regimen, Einhorn found that ifosfamide was effective; in fact, substituting ifosfamide for bleomycin in second-line chemotherapy reduced lung toxicity. Einhorn’s work with the drug helped to move it toward FDA approval.

Finally, his team discovered a strategy for patients whose testicular cancer could not be cured with standard chemotherapy: high-dose chemotherapy with peripheral blood stem cell transplant.

Continuing the Quest

These days, Einhorn, the married father of an adult son and daughter, remains immersed in the work that has captivated him for the last four decades. He spends two and a half days each week seeing patients who have testicular cancer, lung cancer, and “a smattering of rare diseases that don’t fit into any organ type, like cancer primary site unknown.”

He splits his remaining time between lecturing and attending conferences; designing and running clinical trials; and teaching interns, residents, and fellows. Einhorn reminds the students to interact with their patients, despite the distractions of modern technology. “Doctors are turning their backs to patients and clicking away on their computer screens, typing while they are talking,” he said. “That needs to be done, but I don’t want us to lose the ability to communicate with patients and show our real concern for the struggle they are facing.”

Einhorn’s recent work in the fight against testicular cancer is focused on the long-term effects of therapy for the disease.

“Our pediatric colleagues have done a great job, with leukemias and sarcomas, of curing patients and then looking at what the late consequences of therapy are, what their prevalence is, how to predict them, and whether there are preventive strategies,” Einhorn said, “and that’s what we’re focusing on now.”

In addition, Einhorn and his colleagues continue to investigate new drugs for the treatment of testicular cancers that cannot be cured with existing therapies.

At the same time, they are continuing to study psychosocial aspects of testicular cancer. “This is a unique patient population we deal with,” he said, “so we have a lot of collaborators who look at a variety of different aspects, including romantic relationships and fertility issues.”

Becoming a Giant

Einhorn’s interest in becoming a doctor sprouted during high school in Dayton, Ohio, when he accompanied his father, a community physician, on hospital rounds. “He was a good role model,” Einhorn said. “He treated patients with respect, and the respect he got, he earned.”

After earning a BS from IU, Einhorn attended medical school at the University of Iowa. Then, it was back to IU for an internship, residency, and fellowship, with time away from that path from 1969 to 1971, when he served during the Vietnam War treating patients at an Air Force base in Wichita, Kansas.

His service completed, Einhorn returned to IU and his mentor, Robert J. Rohn, MD, who had inspired him to treat patients with cancer. Rohn suggested that Einhorn pursue the research and treatment of solid tumors, possibly as a fellow at MD Anderson, and the young doctor did just that, studying with Emil J. Freireich, MD, and developing an interest in experimental therapeutics.

He returned to IU Medical Center in 1973 as an assistant professor, and began working his way up the ladder at the institution. Along the way came unforgettable experiences, particularly treating John Cleland, the first patient in the world to receive the Einhorn regimen.

“John had failed to be cured with several other forms of chemotherapy and came to me with the idea that we were going to give him platinum,” Einhorn recalled. “We had no idea what it would do, but knew it would come with terrible side effects. To have the courage to go through therapy that makes you that sick without knowing if it will make you live longer, and to do it again and again through four courses, is very altruistic and courageous. Thirty-nine years later, we still keep in touch socially; he’s a friend.”

Countless other patients received the Einhorn regimen, including cyclist Lance Armstrong, whom Einhorn treated and who has since become the world’s best-recognized spokesman about testicular cancer. “He did a great deal of good when he was first diagnosed in increasing public awareness of the disease,” Einhorn said. “Most 25-year-old men had no idea there was such a disease. The Livestrong Foundation, which he set up by himself with his own funds, blood, sweat, and tears, has done a remarkable job of helping the cancer community.” In all his years at IU, Einhorn has never been tempted to leave.

“We have a cohort of investigators here that I couldn’t find at any other place in the world,” he said, “and I don’t think there’s another institution in the country that could have allowed me access to the patient population I’ve worked with, because this is a rare disease.”

Although Einhorn describes his work as a “cruel mistress” that doesn’t leave him much time for hobbies like reading crime novels, playing tennis, and attending sporting events, he enjoys what he does, especially in light of a simple lesson it has taught him.

“In oncology, you learn to appreciate the fact that, as long as you’re healthy, nothing else matters,” he said.

Views of Einhorn’s Work From the Front Lines

Lois B. Travis, MD, ScD

Professor, Department of Radiation Oncology Director, Rubin Center for Cancer Survivorship University of Rochester School of Medicine Rochester, NY

Dr Einhorn’s introduction of cisplatin into medical oncology, with the resultant cure of a metastatic cancer, marks one of the most groundbreaking medical achievements of the 20th century. Other physician-scientists subsequently built on Dr Einhorn’s work and developed other platinum compounds. As a result, the platinating agents are now one of the most commonly used group of cytotoxic drugs worldwide.

Costantine Albany, MD

Assistant Professor, Clinical Medicine Division of Hematology/Oncology Indiana University Melvin and Bren Simon Cancer Center Indianapolis, IN

“Dr Einhorn is more than a mentor to me. One of the first things that I wanted to do when I joined the fellowship program at Indiana University was to introduce myself to Dr Einhorn because he is a nationally and internationally recognized authority in oncology. He immediately welcomed me into his clinic with open arms and thus began a wonderful mentoring relationship. “Dr Einhorn not only cured testicular cancer but also played a tremendous role in improving the quality of life of testicular cancer patients through his research on chemotherapy-induced nausea and vomiting, as well as reducing the toxicity of chemotherapy. “Dr Einhorn is absolutely unique in his ways. He receives hundreds of e-mails daily from patients with testicular cancer, their family members, providers, and fellow oncologists, from the United States and abroad. I do not think Dr Einhorn sleeps until he answers all his e-mails from all who are asking for advice on complicated testicular cancer cases.”

Anuj K. Agarwala, MD

Hematologist/Oncologist Community Regional Cancer Care Indianapolis, IN

“Dr Einhorn’s research in testicular cancer took patients who were in advanced stages with a poor prognosis and improved their cure rate to over 80%. His research helped make the treatments of testicular cancer a gold standard for how we treat cancer today.”

DR EINHORN’S SELECTED REFERENCES

• Al-Hader AA, Jain A, Al-Nasrallah N, Einhorn LH. Metastatic malignant transformation of teratoma to primitive neuroectodermal tumor (PNET): results with PNET-based chemotherapy [published online June 24, 2013]. Am J Clin Oncol.
• Ehrlich Y, Beck SD, Foster RS, Bihrle R, Einhorn LH. Serum tumor markers in testicular cancer [published online September 6, 2010]. Urol Oncol. 2013;31(1):17-23.
• Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stemcell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357(4):340-348.
• Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer [published online April 14, 2007]. Support Care Cancer. 2007;15(11):1293-3000.
• Einhorn LH, Brames MJ, Juliar B, Williams SD. Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol. 2007;25(5):513-516.
• Moore AM, Einhorn LH, Estes D, et al. Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial [published online February 20, 2006]. Lung Cancer. 2006;52(1):93-97.
• Roth BJ, Dreicer R, Einhorn LH, et al. Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 1994;12(11):2264-2270.
• Einhorn LH, Nagy C, Werner K, Finn AL. Ondansetron: a new antiemetic for patients receiving cisplatin chemotherapy. J Clin Oncol. 1990;8(4):731-735.
• Einhorn LH: Testicular cancer: a model for a curable neoplasm. Cancer Res. 1981;41(9 Pt 1):3275-3280.
• Einhorn LH, Donohue JP. Improved chemotherapy in disseminated testicular cancer. J Urol. 1977;117(1):65-69.