I think the advances in testes cancer in the next decade are going to be on the genetic front—identifying patients with a genetic susceptibility that predisposes them to toxicity from the platinum-based therapies that can offer cure.
—Lawrence H. Einhorn, MD
Testicular cancer is one of oncology’s true success stories. It is a highly treatable disease, usually curable, that most often develops in young and middle-aged men. Despite the success in testicular cancer, there are still clinical challenges ranging from staging to optimum therapeutic approaches. To explore these challenges, The ASCO Post recently spoke with internationally regarded testes cancer expert Lawrence H. Einhorn, MD, Distinguished Professor of Medicine at Indiana University School of Medicine, Indianapolis.
What has been the most important advance during your career in testicular cancer?
The most important advance in testes cancer goes all the way back to the early 1970s, with the discovery of the first heavy metal platinum ever used as an antineoplastic agent. Ironically, despite the activity platinum showed in a variety of human tumors, the toxicity was so severe that platinum came dangerously close to being discarded as a therapeutic option.
In some early phase I trials, however, a few testicular cancer patients in whom other treatments had failed were given single-agent platinum, and their tumors regressed substantially. Since the platinum in these patients was given as third-line therapy, the responses were transient and the cancer returned. But following this positive response, we looked at platinum combined with other drugs in first-line therapy. And in 1974, when we began our studies with platinum plus vinblastine plus bleomycin, the cure rate in these young men improved from about 5% to 55%.
In effect, just as platinum has saved the lives of so many men with testicular cancer, testicular cancer “saved” platinum. Because if not for its success in testicular cancer, platinum probably would have been discarded as a highly toxic, minimally effective drug. Now, 40 years later, platinum has become a component of first-line chemotherapy for 11 different tumor types—more than any other single agent.
Clinical stage I testicular cancer is the most prevalent presentation. Have we reached a point of consensus on how best to approach the disease at this stage? And as a follow-up, are we underutilizing active surveillance?
When I see a new patient diagnosed with clinical stage I nonseminoma testes cancer whose computed tomography (CT) scans, serum human chorionic gonadotropin (hCG), and physical exams are normal, I have a discussion about the pros and cons of surveillance vs having a good urologist do a nerve-sparing retroperitoneal
lymph node dissection or having one course of adjuvant chemotherapy. To me, the preferred option in this setting is active surveillance.
In fact, late last year, I was one of 23 authors who published a consensus statement in the Journal of Clinical Oncology that examined all the options in clinical stage I disease and concluded that surveillance was the preferred clinical option. That said, performing a nerve-sparing retroperitoneal lymph node dissection or delivering one course of adjuvant chemotherapy in the stage I setting should still be part of the treatment option discussion between physicians and their patients.
However, in clinical stage I seminoma, where there are three options—a single day of carboplatin, radiation therapy, or surveillance—there is near-unanimous support for the use of surveillance unless there is some compelling reason to the contrary.
Retroperitoneal Lymph Node Dissection
What is the clinical status of retroperitoneal lymph node dissection today?
In clinical stage I disease, the advantage of having a retroperitoneal lymph node dissection is that it indicates whether the lymph nodes are positive or negative for metastatic cancer. Metastatic testes cancer is the most curable of metastatic cancers with chemotherapy, and it is also the most surgically curable cancer in the presence of nodal metastases.
To that end, retroperitoneal lymph node dissection is not just for staging; it’s also a therapeutic procedure. If a patient undergoes retroperitoneal lymph node dissection, as opposed to surveillance, he never has to have another CT scan of the abdomen because you’ve removed those lymph nodes.
So there are benefits to doing retroperitoneal lymph node dissection, but we are doing fewer and fewer in stage I disease, as surveillance has become the preferred option. But if a retroperitoneal lymph node dissection is called for in a younger patient, it’s important to have a urologist who has expertise in doing nerve-sparing retroperitoneal lymph node dissection, in order to spare the patient from retrograde ejaculation and infertility.
Where are we in the management of patients at high risk of recurrence?
Patients who have stage I disease with vascular invasion are at high risk for recurrence. We are still very comfortable with active surveillance in this setting despite a 50% chance of disease recurrence, because even if disease recurs, we can cure 99% to 100% of these patients with standard chemotherapy for metastatic disease.
Patients with a high risk for recurrence are those who have a high risk of never going into complete remission with their chemotherapy. For many decades, four courses of the combination regimen BEP (bleomycin, etoposide, and cisplatin) has been standard first-line therapy for metastatic testes cancer.
In fact, at last year’s ASCO Annual Meeting, a French group presented a study in which the half-lives of serum hCG and alpha-fetoprotein were assessed during the first course of therapy.1 Patients in whom these measures were not decreasing appropriately (based on a fairly complicated algorithm) were randomly assigned to continued BEP vs a six- or seven-drug concoction with additional courses of chemotherapy. There was no difference in overall survival between study arms, but there was an advantage in progression-free survival among those receiving the additional agents.
We haven’t adopted that approach in the United States, and we are still looking to find a better treatment than standard BEP in first-line chemotherapy. However, when a patient does relapse, we have curative options—standard-dose platinum along either with drugs they haven’t had before or with very high-dose chemotherapy followed by a stem-cell transplant. Even in the salvage setting, we’re still going to cure more than 50% of these patients who relapsed after their first-line treatments.
Are there ongoing studies that the readers should be aware of?
In testes cancer, most of our patients present with clinical stage I disease, and statistically we cure more than 99% of those patients. We’re not going to improve outcomes in that setting. Moreover, we cure about 95% of patients with good-risk metastatic disease. We’re not going to improve those outcomes, either. But we’re always looking for ways to improve the 50% cure rate of patients with very advanced disease and new methods of delivering salvage chemotherapy.
In our group, we’re looking at the late consequences of platinum-based chemotherapy, such as neuropathy, cardiovascular toxicity, and second malignancies. These are survivorship issues that we don’t think about at the time of diagnosis because we’re just trying to get our patients through their therapy and cure the cancer. But these are important quality-of-life issues in the post-therapy setting that need to be studied.
Any last thoughts on this clinical area that you’ve devoted much of your career to?
I think the advances in testes cancer in the next decade are going to be on the genetic front—identifying patients with a genetic susceptibility that predisposes them to toxicity from the platinum-based therapies that can offer cure. In the early days of platinum therapy, drugs were eventually developed to ameliorate the horrendous side effects of nausea and vomiting. I see a time in the near future when we’ll be able to identify patients at risk for the chronic side effects of therapy, and have the personalized tools to treat those side effects. So the future is bright in testes cancer. ■
Disclosure: Dr. Einhorn reported no potential conflicts of interest.
1. Fizazi K, Pagliaro LC, Flechon A, et al: A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ cell tumors: Results of GETUG 13. ASCO Annual Meeting. Abstract LBA4500. Presented June 1, 2013.
Gifts totaling $1 million in honor of the 40th anniversary of the cure for testicular cancer were recently announced at a celebration for the physician scientist who developed the treatment. Family, friends, colleagues, and men grateful for their lives gathered at the Indianapolis Museum of Art to...