The Cancer Letter asked Lawrence Einhorn, distinguished professor of medicine and the Livestrong Foundation Professor of Medicine at the Indiana University Melvin and Bren Simon Cancer Center, to reflect on one of the most spectacular successes in the history of cancer research—his development of the curative regimen for testicular cancer.
Einhorn spoke with Matthew Ong, a reporter at The Cancer Letter.
Matthew Ong: What was it like to meet John Cleland 40 years ago?
Lawrence Einhorn: John himself, as a patient, looked fine, and that’s one of the paradoxes with young, healthy men with testicular cancer.
Even up until the last couple weeks of life, they actually look pretty well.
But certainly, without chemotherapy, John’s chances of surviving more than a year was basically zero. His chest X-ray looked much worse than he looked, as far as just looking at him walking down the street.
Like so many patients then and now with testicular cancer, you see these round, white, kind-of-like snowballs scattered throughout the right lung and the left lung.
It somewhat amazes me—you look at that chest X-ray and you think that someone can barely breathe, but again, a young, healthy person who is their 20s is very different from an elderly debilitated person in their 80s as to how they can handle the burden of disease.
What uncertainties did you face when you first put John on the combination regimen?
LE: When you’re using an experimental drug that had never been combined with other drugs and you’re sort of the first person—John Cleland—to get that, A, you have no idea whether the drugs can be combined safely, B, you have no idea if it’s going to help them and cause a remission, C, you have no idea how long that remission is going to last, and D, we never pronounce a cure three weeks after someone starts treatment.
How hopeful were you that your treatment would work, three weeks into administering the drugs?
LE: To be honest with you, most of the time, when an experimental drug is combined with other drugs—and this was fourth-line therapy for John; he had failed to be cured although he responded to three previous types of chemotherapy—even today, in 2014, if you’re using a treatment that is fourth-line therapy and you look at a chest X-ray three weeks later to see how pulmonary metastases are doing, it’s going to show further progression.
The first level of excitement was seeing that, ‘My God, something is actually helping.’
Now, in October [1974], we had no idea whether the benefit was going to last a month, six months, or, in John’s case, fortunately, and for many thousands if not hundreds of thousands of patients, wind up being a curative treatment for this disease.
What was it like to see John’s X-ray after that first treatment?
LE: Well, it was equally exciting—and that’s probably the wrong word—obviously, it’s more exciting for the patient, but it is very exciting for an investigator to see that an experimental type of treatment in a very, very heavily pre-treated patient who really has no treatment options other than this clinical trial, actually is showing, at least on a short-term basis, that tumors that were rapidly growing in the lungs are now regressing in the lungs to where they were barely visible at the three-week level.
Would you say that your combination therapy was one of the biggest breakthroughs in treating solid tumors?
LE: Well, actually, it’s not often in solid tumors—as opposed to immunological malignancies, like leukemia and lymphoma—that you can, not just cause remissions, but also actually cure patients with the disease.
Prior to platinum, with some of these older drugs, the cure rate was 5 percent. Today, with platinum-based chemotherapy, it’s gone from 5 percent to 80 percent, and that’s been unprecedented—even 40 years later—to have that type of leapfrog benefit.
In retrospect, what do you know now about cancer that you didn’t then?
LE: In the 1970s, our knowledge was very rudimentary, and perhaps very naïve. And we’ve learned a great deal through genomic research, about the molecular basis and pathogenesis of cancer, and we’re learning more and more that, instead of calling something testis cancer or lung cancer or breast cancer, or colon cancer, that we’re looking at the specific mutations that drive the pathogenesis of the disease.
And instead of using chemotherapy—and again, chemotherapy with platinum is always going to be the standard for testicular cancer—but instead of just looking at chemotherapy, which is sort of non-specific, we personalize therapy, to give a drug that is specifically designed for whatever it is that’s driving that particular patient’s mutation.
There have been some outstanding successes like imatinib and chronic myelogenous leukemia and gastrointestinal stromal tumors, certainly Rituxan and lymphomas, and Herceptin and breast cancer. These are all known molecular-based therapies, rather than in 1970s, where we simply took a chemotherapy drug off the shelf and combined it with other chemotherapy drugs and hoped for the best.
Was that what you did with cisplatin?
LE: Basically, then and now, when you combine drugs, you want drugs that are known to have single-agent activity, and platinum was a single agent, and in patients who have been through previous therapies was producing remissions, but no cures. Remissions were always very brief and temporary, and the toxicity was very severe with platinum.
Then you want to combine drugs that kill cancer cells by different mechanisms of action, and you want to combine drugs that have different side effects—you don’t want three drugs in a combination that have the same side effect, or you won’t be able to use them at full dosages.
You want to combine drugs that play together well in the sandbox that are not just additive, but what we call ‘synergistic,’ so one plus one isn’t just two. This was certainly true with the platinum combination chemotherapy regimens, and that philosophy for chemotherapy 40 years later is still true today.
At what point did you realize that cisplatin was this good in testicular cancer? Did you have a gut feeling before you ever gave it to patients?
LE: I think those of us who are medical oncologists, who are involved in clinical trials, tend to be more optimistic than pessimistic. But we’re also realistic. It is unusual—looking at John Cleland—even today, to have an experimental drug, or combination of drugs and ever cure anybody when it’s fourth-line therapy, as opposed to first-line therapy.
So the first clue that it was doing something happened three weeks later in two different aspects:
Number one, the fact that we could actually combine these drugs safely, because it’s not a given that you can put platinum together with other drugs and not produce overwhelming side effects that can be tolerated.
The second clue was, instead of further progression—which is what would’ve happened if he wanted no therapy—he was actually in remission. And then the third clue was, the nature of testicular cancer is such that when a patient is out at one year, it’s unusual for the cancer to come back.
But until someone is out at one year, and that would be not October 40 years ago, but October 39 years ago, then you have some optimism that John, as a single patient, is cured of his disease.
But then you need a larger number of patients to know that this is not just a medical curiosity for one anecdotal patient, but that actually works across a cohort of patients.
So it wasn’t until we had about 20 patients out at over a year, that we really did appreciate the fact that this was not just producing several months of remission in a couple of patients, but this was actually making a major difference forward and curing the majority of patients with testicular cancer.
This was a good two years or so after John became the first patient to be cured with platinum-based chemotherapy.
Before John, did you treat other patients with this regimen?
LE: We had one patient before him, and this is another heavily treated patient that was more critically ill than John was. John actually looked pretty healthy, and this patient died within the first three weeks.
Whether that was partly from the drugs, or more likely, mostly from the tumor, it’s difficult to know. And again, when you start a new type of treatment, as I said before, there’s no guarantee that you can even give drugs safely when you combine different drugs.
The nature of experimental trials is, you’re not going to use them as a brand new experimental drug that’s never been used before at a combination on a perfectly healthy patient who’s never had any other type of treatment before, most of the time.
There are patients who have been through previous types of treatment, especially if an older treatment has some degree of efficacy.
What did you do to reduce the combined toxic effects of your regimen?
LE: If a drug works, as a science, we learn how to mitigate the side effects. So the most horrendous side effect, initially, was the incredibly severe nausea and vomiting, so we and others have worked at developing selective drugs that don’t eliminate platinum-induced nausea and vomiting, but greatly reduce the amount of nausea and vomiting that people have.
When John was getting treated, and we didn’t have any of those drugs then, the average patient would have 12 emetic episodes. They would vomit 12 times on day one of a five-day course of chemotherapy.
And today the average patient on day one would get some degree of nausea, but usually will have zero episodes of vomiting. So the nausea and vomiting worked out very well.
The second thing had to do with the drug causing kidney failure, which is a more serious side effect—not as troubling to a patient as nausea and vomiting—but more serious, perhaps even fatal.
And so we quickly learned that platinum was a heavy metal like mercury and other heavy metals, and that we can prevent the kidney damage by just making sure that we give lots of intravenous fluids before we gave the platinum and after we gave the platinum.
It became a pretty simple method to reduce the nausea and vomiting and reduce the potential life-threatening kidney damage once we and others had a little bit more experience with the drug.
And then as the years went by, we learned that we can reduce the dosages of some of the drugs, shorten the duration of therapy without reducing the therapeutic results.
When John was treated, the duration of therapy was much longer than it is today, because we’ve done phase III clinical trials demonstrating non-inferiority with lower dosages—the platinum hasn’t changed—but lower dosages of the drugs, and shorten the duration of the therapy.
Did you lead most of these studies as well?
LE: Indeed, yes.
Is there any way to repeat your success with other cancers? What leads can oncologists and researchers follow today?
LE: Sure. And again, 2014 is very different from 1974, and I think I still harbor hope that similar success stories with other epithelial cancers will be produced, but probably not with chemotherapy.
It will be with specific molecular targeted agents or—what’s very red-hot in the last couple of years—with immune checkpoint inhibitors to stimulate the immune system and figure out what drug works best for an individual patient, and also to hopefully figure out whether it can be safely combined with other drugs and produce results.
You’re saying that the future is in genomics, immunotherapy, and molecular targeted therapies.
LE: Exactly. And there’s always some role for chemotherapy, and drugs like platinum aren’t going to be replaced by molecular targeted agents, but I think the new, yet-to-be-discovered drugs will probably be non-chemotherapy molecular targeted agents, and drugs that affect the immune system.
I think in the last 10 years, the advances that have been made for patients in successful treatment have been phenomenal, and there’s virtually no form of cancer that we deal with in 2014 that we don’t, at the very least, relieve symptoms and produce palliation and prolong survival.
Now, in 2014, we don’t have an 80 percent cure rate in any disease other than testicular cancer as far as a solid tumor, but we’re moving forward, and that’s the main thing.
