Clinical Trials and Developments in Testicular Cancer - Darren Feldman

April 27, 2021

Darren Feldman, MD, and Charles Ryan, MD, discuss multiple topics in this conversation on testicular germ cell tumors ranging from risk factors, developments in treatment, and the global TIGER study. There is limited data for the association of testis cancer with hereditary cancer genes. In this conversation, Daren Feldman highlights developments in treatment for testicular cancer including the introduction of microRNAs, particularly the miR-371a-3p which has demonstrated excellent performance in testicular disease. Serum microRNAs have emerged as a highly sensitive and potential addition to markers used in testicular germ cell tumor management. Addressing Dr. Ryan’s question on imaging in this disease space and the risk of CT scans, Dr. Feldman highlights the phase III TRISST trial, The Trial of Imaging and Surveillance in Seminoma Testis, which assessed whether CTs can safely be reduced, or replaced with MRI, without an unacceptable increase in advanced relapses. They also discuss the global TIGER study. A randomized phase III trial of TIP vs TI-CE as initial salvage chemotherapy for patients with germ cell tumors. Dr. Feldman reports this trial is currently 80% accrued.  The TIGER trial is a randomized Phase III study that is going on all over the world. It's being conducted in three continents and, I think, at last check 13 different countries around the world including North America, Europe, and Australia/New Zealand. It's a study for patients who have germ cell tumor, whether it started in the testicle or extragonadal and have progressed after first-line chemotherapy, typically with bleomycin etoposide cisplatin, BEP, or etoposide cisplatin EP or VIP.

Biographies:

Darren R. Feldman, MD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Charles J. Ryan, MD, The B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology, and Transplantation, Minneapolis, Minnesota


Read the Full Video Transcript

Charles Ryan: Hello and welcome. I'm delighted to be joined by Dr. Darren Feldman, who is an Associate Attending at Memorial Sloan Kettering Cancer Center, where he is also the Section Head for germ cell tumors there, so there is no greater expert on the planet, I think, to talk to us today about the emerging field of the treatment of germ cell tumors in testicular cancers, as we face testicular cancer awareness month. Darren, great to have you with us today.

Darren Feldman: Great to be here. Thanks so much.

Charles Ryan: There are a few new things to talk about that I want to get to, but before we do that, what would you counsel a healthy young 30-year-old man about his risk for testicular cancer, what they should watch out for, and what are the most common presenting symptoms that a person may have?

Darren Feldman: Great. So, the lifetime risk for a man in the US is about 1 in 250, roughly. So most men will know someone who has had testicular cancer, a friend of a friend, or a family member, or someone in their life who has had testicular cancer, even if it's a second or third-degree away from them.

The biggest risk factor for testicular cancer is being born with an undescended testicle. And even if the testicle is brought down surgically through an orchiopexy at a young age, it doesn't eliminate the risk of the development of testicular cancer. I find that, for whatever reason, most parents, and then the patient themselves, when they have had cryptorchidism and ultimately developed testicular cancer, weren't actually even aware that they were at an increased risk. So hopefully we can get the message out that those patients, in my view, should be doing self-exams and understand that they are at a higher risk.

The other major risk factor is having a family history of testicular cancer, and especially a brother. I estimated that about a 5 to 9-fold increased risk over the general population. So if you want to say 2% to 4% chance, lifetime, of developing testicular cancer if you have a brother who has had that diagnosis. From father to son it's a little bit lower, probably 2 to 5-fold, increased risk. And of course, even within brothers, fraternal twins, or identical twins, the risk increases significantly.

Charles Ryan: But my understanding is we don't have a gene test for that risk, we just know that family history increases risk, correct?

Darren Feldman: That's correct. We and others are studying germline DNA on patients who have a family history of testicular cancer with more than one relative, as well as patients who have bilateral testicular cancer, which I know is something we are going to talk about later, because the thinking would be that there would likely be some sort of genetic underpinning to why it would happen in multiple members of the same family, or potentially in both testes. But we haven't been able to definitively solve that. There are a couple of single-nucleotide polymorphisms, such as in the c-kit ligand, that have been associated with an increased risk of testicular cancer, but we don't have the familial gene. There is no BRCA1 or BRCA2 for testicular cancer.

Charles Ryan: Not yet, but maybe someday?

Darren Feldman: Maybe someday.

Charles Ryan: I understand there has been a shift in what we would call the demographics of the disease in the US, shifting, perhaps, a little bit towards a Latino population. Is that correct?

Darren Feldman: Yeah, over the last 60 years or so, there has been an increase, almost a doubling, of the incidence of testicular cancer in the United States, but it's been barely flat amongst Caucasians for the past one to two decades. In contrast, it's been increasing significantly among Hispanics. And I did read one article that suggested that by 2026, per capita, there will be a higher incidence among Hispanics than Caucasians. Traditionally, we thought of Caucasians as the highest risk demographic, followed by Hispanics, and then it is much less common in African-Americans.

Charles Ryan: Yeah. Interesting, interesting. That may reflect just changes in the population overall, but what I guess you are saying is that even as the population changes, the proportion of men within the populations who are destined to get this disease may actually be going up in a Hispanic population.

Darren Feldman: Yes, that's correct.

Charles Ryan: And still, for the most part, most people who are diagnosed do so themselves. They self-identify through a testicular self-exam that they do. Is that still the case?

Darren Feldman: That's right. I want to get back to answering your initial question about, what are the signs and symptoms of testicular cancer? The most common, or the textbook answer for the presentation of testicular cancer, would be a painless testicular mass that someone might notice in the shower when they are washing or if they sit in a certain way and feel a little less comfortable. But it's much more common to present with a painful or swollen testis, and the differential diagnosis there is between epididymo-orchitis, inflammation of the epididymis in the testicle, and testicular cancer.

And so it's important that even if there is pain, which could represent either diagnosis, that that be evaluated. We find that many men are embarrassed or just delay going to the doctor. This is, when found early, an extremely curable cancer with limited morbidity, but when found later, it remains curable, but with a much higher toll on the patient. So we want patients to present early. They should present to their doctor. Their doctor should evaluate, potentially, for the diagnosis, they can give a course of antibiotics, for example, for a 2-week course. But if the patient doesn't improve, they need to see the patient back. And if they don't improve, an ultrasound is necessary, and it would also be reasonable to get an ultrasound right away on those patients.

Charles Ryan: I see a lot of men who are upset that they were given antibiotics first and think their doctor missed the diagnosis, but actually their doctor was following a pretty standard protocol to treat with antibiotics first, and then just as long as the person is followed up with an ultrasound or a follow-up exam. Very good.

I want to talk to you about a couple of the things that are developing. There is a lot of different ways that men with this disease can be treated based on the stage, and based on the type of testicular cancer they have. For the most part, people are starting with surgical removal of the testicle. Some get chemotherapy after that, but most who just have a stage 1 disease will go on surveillance. My understanding is there are some new biomarkers, microRNA, and other things, that can be used to try to identify the risk of recurrence in patients being diagnosed? Tell us about that?

Darren Feldman: Probably the most exciting advance that we've had in this disease in quite some time has been the introduction, at least in a research basis, a test called microRNA 371-3p, or just 371. MicroRNAs, just for those who aren't familiar with it, are non-coding small RNAs, they are usually about 19 to 21 nucleotides. So instead of like most RNAs, which are messenger RNAs and get translated into protein, these do not get translated into protein. Their function is actually to bind to other messenger RNAs and prevent the translation of the protein. And once microRNAs were established and discovered, there were, amongst a broad field of cancer types, investigations into whether there were specific microRNAs that were found in one tumor type versus another.

Seminal studies led by Matt Murray and others from the University of Cambridge, and other European groups, discovered that there was a cluster of microRNAs, including 367 and 371 to 373 that were found in the tumor tissue of patients with testicular cancer. And then also, more importantly, in the serum, at a very, very high level of correlation between testicular cancer and those levels in the serum.

So over 90% of patients with testicular cancer at diagnosis will have an elevation of this blood marker in their serum or plasma. And if you think about how that compares to AFP and HCG, the conventional tumor markers that we have, in non-seminoma, about 60% to maybe 70% of patients will have an elevation of one of those markers, and in seminoma, it's more around 35% or so. So you have a new marker that has 90% or greater detection, versus much less for established markers.

Now, it's not, it's not perfect microRNA, but it's very exciting in that context to be able to differentiate between a testicular tumor and a non-testicular tumor. Actually, studies showed that patients with non-germ cell testicular cancer, so Leydig cell and Sertoli cell tumors and other benign testicular entities, do not express these markers, and so it's very specific to actually germ-cell tumors within the testis.

There's a whole range of potential research applications and clinical applications to this. As you can imagine, for someone who has stage 1 disease, if they have that marker and it's elevated at the time of their diagnosis, then they have their orchiectomy, it should go to normal. And then that could be followed to screen them as part of surveillance. That might eventually be able to take the place of CT scans or other imaging techniques if it's that good of a marker. In addition, it's possible that you can evaluate response to chemotherapy with this marker, you might be able to predict who needs surgery after chemotherapy and who doesn't base on the likelihood of having live cancer remaining.

One other thing to mention is the half-life of this microRNA is very, very short, so changes happen very quickly. And so it's very useful from that standpoint as well. Even within 24 hours to 48 hours after orchiectomy, the marker essentially disappears, and that there is no residual cancer.

Charles Ryan: It sounds really promising, but this is not in the clinic.

Darren Feldman: Correct.

Charles Ryan: This is not something that the regular patient outside of an academic center or a research study can get. What are the steps required to get it to that point? And will that happen in the next couple of years?

Darren Feldman: Great question. Some of that will be up to regulatory authorities, but the studies that have been done so far have either had a small number of patients, or they've had a large number of patients, which have mainly looked at the microRNA levels in a diagnosis, and not as much through the trajectory of cancer in terms of monitoring for surveillance and other aspects. So, I think that it's going to take clinical trials, like some that are ongoing now.

There is a COG protocol that is open to adults as well, looking at stage 1 non-seminoma patients, it's called AGCT1531. Patients with non-seminoma are put on surveillance, get the microRNA checked at specific time points, and we are going to look to see if that correlates with relapse and if it picks it up earlier than a scheduled standard surveillance schedule of imaging. And if it does, that type of study will definitely lead to acceptance in that setting. But I do think it is probably going to have to be demonstrated in a specific setting to be established as a marker, and then once it is established as a marker, it will be used in all kinds of settings, but it will have to be validated in those other settings.

Charles Ryan: Right, right. So, many years of research, I would imagine, asking questions like should you treat people with the microRNA-positive disease with chemotherapy? Or should you do RPLNDs? And how soon do they need to be imaged? Things like that.

On the imaging front, a lot of men who are diagnosed with this and have to have surveillance scans after their orchiectomy raise concerns about the risk of CT scans. So, reducing the number of CT scans might be advantageous. What do you tell patients about the risks of CT scans, when you are in your twenties and you're going to have a number of total-body CT scans over the course of several years?

Darren Feldman: That's a great question. And I also think that question was highlighted and a recently reported research study at the Genitourinary Cancers Symposium in February, called the TRISST study, that was presented by Robert Huddart. And that study looked at CT scans versus MRI, MRI, of course, being with [inaudible 00:13:34] as compared to CT scan. That study found that an MRI had essentially as good, or maybe even better detection of recurrence. The endpoint was whether the patient would recur with stage 2C or higher disease, a more advanced disease. And so it was no worse, certainly, with an MRI than it was with a CT.

What I tell patients is that the evidence or harm from CT scans is largely indirect. It is based mainly on mathematical modeling of people who were exposed to a nuclear explosion, such as Chernobyl, and then were followed very closely by the World Health Organization, for example. We know, by the rate of decay and how far away they live from the epicenter of the explosion, how much radiation they were exposed to. And then those patients were followed and those cities were followed, and then you can see what the increase in cancer risk was amongst those patients. And then you can extrapolate back to say, "You were exposed to this much radiation and you had this much-increased risk of another cancer, and then this many CAT scans is equal to that much radiation." And then there have to be some mathematical models to adjust for the fact that when you are exposed to an explosion, you get all of the radiation doses essentially at once, whereas with a CAT scan you get a little radiation, you get more, is it the same?

So it's indirect data. What we really need is direct data of patients followed for 20 or 30 years after getting anywhere from three to eight cat scans over the course of their surveillance, and seeing if that causes an increase in other cancers. My personal belief is that there probably is some risk. I'm not sure exactly how to enumerate that risk, I think there are probably some elevated risks. I think that with the results of the TRISST study, MRIs may become a more acceptable alternative to CT scans. It is a longer test that is not for patients with claustrophobia, it's a more expensive test, so there are additional questions. It is not a test that is easily read by a medical oncologist like you and me. We have a lot easier time reading a CT than an MRI. So there are a lot of questions that remain, but that is becoming a viable alternative.

Charles Ryan: Yeah, and that latter point is an interesting one. I always look at my patient's scans when they come in with them and I've told them, in the cases where I've gotten MRIs, that I can't help. I have to have a radiologist. So, very good.

So tell us, finally, you are leading a major, really important international study called the TIGER study. It's been a huge amount of work and continues to accrue patients, I believe. This is, of course, for platinum-refractory patients who have already received upfront chemotherapy. Tell us about the progress on TIGER.

Darren Feldman: Great. Thanks so much for highlighting this study. I do believe this is a really important study in the field for patients who have progressed after first-line chemotherapy, which generally consists of etoposide and cisplatin, with or without bleomycin or ifosfamide. The standard of care has been subject to controversy when you progress and need second-line chemotherapy, with some experts favoring and giving standard-dose salvage chemotherapy regimens, such as TIP or VeIP, and others favoring going straight to high-dose chemotherapy with stem cell transplant.

And unfortunately, there has only been one randomized trial that's been conducted to try to answer that question called the IT-94 study. It found no difference in outcome between patients who were treated with one single cycle of high-dose chemotherapy after three cycles of standard-dose chemotherapy, versus just four cycles of the same standard-dose chemotherapy. There was no benefit, and so that led a lot of people to use high-dose chemotherapy as the third-line.

The hypothesis of this study is that giving high-dose chemotherapy earlier, as second-line, would lead to greater overall survival and benefit to the patients. The differences are that in that prior study, they only used one cycle of high-dose chemotherapy, almost every regimen that has shown really significant benefit with high dose chemotherapy has had two or three cycles. So, that is a critical difference. In addition, patients who had been refractory to their initial chemotherapy, meaning they never got into a remission that lasted at least 3 or 4 weeks, were excluded from that other study. And that is a significant proportion of the patients who we see who need second-line chemotherapy, they weren't even included in that study. There were about a little over 25% of the patients assigned to the high-dose arm, who never got the high-dose cycle, and it was a small study with only a little over 100 patients in each arm, so that is a significant problem.

These shortcomings of that study really mean that we don't have a good prospective randomized trial to answer that question, and retrospective data, including a large, almost 1600-patient study, by the International Prognostic Factor Study Group team found that high-dose chemotherapy, as initial salvage, was associated with a significant benefit in progression-free and overall survival. And so the retrospective data conflicts with the one prospective randomized study.

And so the TIGER study is really designed to definitively answer that question. It's enrolling 420 patients, and it is randomizing them to TIP as a conventional-dose standard salvage chemotherapy regimen, or high-dose chemotherapy with stem cell transplant using the TICE regimen, which uses a triple transplant scheme and overall survival as the primary endpoint. That study has accrued 341 patients so far out of the planned 420, so it's a little over 80% accrued.

Charles Ryan: That's great to hear.

Darren Feldman: It has been a huge global effort. It is open in over 13 countries, 3 continents, so all across Europe, the United States, Australia, New Zealand, and it has really been a global collaboration. So, I'm hoping, no matter what this study shows, we will learn something. If high-dose chemotherapy is not superior then we will spare patients significant excess toxicity of high-dose chemotherapy, getting that at second-line, and patients can get a standard dose as second-line. If it's beneficial in survival, then obviously we will have improved survival. And if it works for a certain subgroup of patients, then we may have risk-tailored algorithms, as we do in the first-line setting.

So I think independent of the answer, we will learn something. And there is also a big correlative science aspect to the protocol, this should be the largest repository of cisplatin-resistant tumors for this disease. If we can even get 75% of patients to have a tumor sample, that is going to be over 300 patients with cisplatin-resistant, and we can start to really try to dissect which platinum-resistant patients do well with salvage chemotherapy and which don't, and try to get to that underlying biology.

Charles Ryan: It's one of those studies that whether it's positive or negative in terms of the comparison, it's going to inform clinical treatment and understanding of the biology of the disease. And it is in many ways, a study that is a victory either way. If we have to intensify treatment and improve survival, great. We accomplish that. If we don't have to intensify treatment because it doesn't improve survival, we will spare a lot of people unnecessary treatment.

Darren Feldman: Absolutely.

Charles Ryan: Congratulations on that work. It's been a long road for you, continuing road, I should say, and we really look forward to seeing those data and talking to you about it in this forum in a couple of years, maybe.

Darren Feldman: That would be fantastic.

Charles Ryan:  All right, Darren Feldman from Memorial Sloan Kettering, a real pleasure to have your expertise with us today.

Darren Feldman: Thank you so much.

Charles Ryan: Yeah.