Larry Einhorn, pioneer of platinum-based chemotherapy, discusses 50 years of cancer treatment innovation

When Larry Einhorn was a young physician in the early 1970s, actinomycin-D was the standard drug used to treat testicular cancer. It was—and still is—the most common carcinoma in young men ages 15-35. 

The drug, alas, only provided a 5% to 10% cure rate, Einhorn said on Oct. 20, in a keynote address at the Association of American Cancer Institutes/Cancer Center Administrators Forum annual meeting. 

“What revolutionized the cure rate…is cis-diamminedichloroplatinum (cisplatin or “platinum”), the first heavy metal ever to be evaluated as an anti-neoplastic agent,” said Einhorn, a distinguished professor, professor of medicine, and the Livestrong Foundation Professor of Oncology at the Indiana University School of Medicine. 

An early phase I study of cisplatin, published in 1974 by Roswell Park researchers, produced promising results in 11 patients with refractory testicular cancer who had previously been treated with actinomycin-D, vinblastine, and bleomycin. Three patients showed partial responses, and three achieved complete remission. 

So, Einhorn implemented a treatment regimen of cisplatin, vinblastine, and bleomycin—or PVB—in a new clinical trial. 

“I was…amazed that the introduction of an experimental drug literally had a one logarithmic increase in the cure rate, going from 5% in a contemporaneous actinomycin-D to 64% in this original phase II clinical trial,” Einhorn said. 

Einhorn and colleagues soon started to hypothesize that the new regimen’s success largely came from cisplatin. In their second and third studies involving the heavy metal, the researchers discovered they could lower the dose of vinblastine and eliminate two years of maintenance therapy.

But in the 1980s, Einhorn and colleagues uncovered an even better drug combination. They found that bleomycin, cisplatin, and the novel drug etoposide—a blend called BEP—boosted the number of patients who remained disease-free, compared to those on PVB. “After this study was completed, PVB became a historical footnote,” Einhorn said.

Still, the BEP treatment regimen came with toxic effects, including “horrible” nausea and vomiting, cumulative pulmonary toxicity, anorexia, and neurotoxicity, Einhorn said. So, he led a study in patients with favorable-prognosis disseminated germ cell tumors that suggested the number of treatment courses be reduced from four to three. 

“In a mere 12 years—not by guess and hypothesis, but by well-designed clinical trials—we demonstrated that we no longer need two years of maintenance therapy, that we can cure the patients with just 12 weeks and four courses, that etoposide is better than vinblastine and also less toxic,” Einhorn said. “And for the 60% of patients needing chemotherapy because of disseminated disease—and those are the 60% with good-risk metastatic disease—nine weeks is sufficient to cure their disease.”

BEP is not for everyone, though. 

Einhorn helped treat former road racing cyclist Lance Armstrong in the 1990s, and former cricketer Yuvraj Singh in the 2010s. These athletes received a regimen of VIP—etoposide, cisplatin, and ifosfamide—which has similar effectiveness to BEP, but is far more toxic. However, VIP does not affect pulmonary function, crucial to athletic performance, while the bleomycin in BEP does.  

“We talk today all the time about personalized medicine, looking at genomic characteristics, but personalized medicine sometimes is personal,” Einhorn said. 

Today, cisplatin is the first-line therapy for around a dozen different malignancies. Einhorn’s work on platinum-based chemotherapy in testicular cancer helped pave the way. 

Prior to 1974, “platinum was about to be thrown out. It had some activity in some common diseases, but the toxicity was overwhelming,” Einhorn said. “I doubt that this drug would ever have made it to further human trials were it not for the activity of the drug in testis cancer. And if a drug works, we usually can find, as a scientific community, how to mitigate the toxicity.

“Just as platinum has saved the lives of thousands, tens of thousands, hundreds of thousands of young men with testis cancer, testis cancer saved platinum.”