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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, Dr. Sia Daneshmand, who is the Director of Urologic Oncology and a Professor of Urology at the University of Southern California. Thank you so much for being here with me today.

Sia Daneshmand: Thank you, Alicia. It's a pleasure to be here.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about some of the discussions that you held or gave at ASCO 2021, where you really commented on some of the longer-term outcomes of patients with testicular cancer. Can you tell us a little bit about what you discussed and the two abstracts that you were able to focus on?

Sia Daneshmand: Sure, absolutely. So these were very interesting abstracts focusing on long-term follow-up of testicular cancer patients, which is a topic of interest to many survivorship issues now that we've attained such great outcomes for these patients. So the first one was abstract 5006, Testicular Cancer in the Cisplatin Era: Causes of Death and Mortality Rates in a Population-Based Cohort. And this comes from the Norwegian Cancer Registry, which as you know is an outstanding registry that has really great follow-up for all these patients, and much of what we know for long-term data in testicular cancer comes from the Scandinavian registry. So this was again, the Norwegian Cancer Registry with over 5,700 patients in it, and they looked at specifically non-testicular cancer deaths. There were 665, which was 12%, non-testicular cancer deaths. And as we've known, these are mostly from secondary malignancies, but the excess mortality was 23% compared to the general population, which is pretty significant.

I hadn't quite appreciated the magnitude of the increase until now. And of course, as we know, it increases with chemotherapy and radiation therapy, but not with surgery, as it makes sense. They looked at all these standardized mortality ratios that increase with time. The longer they are followed, obviously, the higher the rate of cancer. And again, the most important cause of death with these non-testis cancer-related secondary malignancies in the oral pharynx, esophagus, lung, bladder, and leukemias with chemotherapy and with radiation therapy was oral pharynx, stomach, liver, pancreas, and even bladder. And I've seen some of those patients, now they are in their 70s, developing bladder cancer, had testis cancer earlier in their years, and got chemotherapy as their treatment. Also, one more interesting thing that came out of this, there were excess suicides seen after chemotherapy, and we've known this as well, that after a cancer diagnosis, the rate of suicides goes up, but this was the first time that I had seen this in the testis cancer cohort.

Alicia Morgans: So it's so interesting and so important to have this follow-up to really reflect back to us as a large group what is happening with this group of patients. And I wonder, from your perspective, if this may affect the way that we take care of patients with testicular cancer in our survivorship settings. Should we be focusing on screening for these secondary malignancies or raising awareness or doing something there? And of course what are your thoughts on mental health in this population?

Sia Daneshmand: Yeah, excellent questions, Alicia. I think absolutely this frames not only our discussion but what we're going to do with these patients after five and ten years. Oftentimes after five years, great, you're cured, your chances of relapse at this point are very, very low, but this certainly frames the discussion in a different way. A, we need to follow these patients longer. We will, I think, discuss the second abstract in a little bit, but second is I think education, for not just a community of people who are the physicians who are going to be taking care of these patients, but also importantly, the patient themselves, himself. If they know what the risks are, perhaps they can be more vigilant about follow-up, make sure they have an annual follow-up, physical examinations, laboratory, and just be aware. It's hard to screen for many of these cancers, you know better than I do. Some of these cancers are difficult to screen, pancreas and even bladder.

So I think just raised awareness, if you ever have hematuria, if you ever have blood in the urine, if you ever had mid abdominal pain, a gastric type of pain. So that's important. Another thing that comes into play here is that now we know about these things when we see stage two cancer, and you and I have discussed this before, one of the options is either chemotherapy or surgery, for instance, into a non-seminoma. And now we can frame this discussion, a little bit more individualized sort of discussion with a patient that surgery as an option does not increase your secondary malignancy rates, and chemotherapy, while very effective in treating stage two germ cell tumors may have an effect on your future, not just fertility, but secondary cancers and other late side effects of chemotherapy.

So more and more I'm sort of shifting my focus towards surgery and that therapeutic window of what we used to say, "Well, what is that percentage of cure that we need with surgery for it to become an option?" Surgery is much less morbid than it used to be. If I tell you that you have a 70% chance of cure, 60% 50%, where is that cutoff where you say, "That's acceptable for me to avoid chemotherapy." Now, interestingly, the significantly elevated risks for non-testis cancer death were seen after four cycles of chemo. So perhaps maybe doing surgery, and in the new microRNA era, if we find patients have a persistent microRNA positive disease, perhaps we can offer them two cycles of adjuvant chemotherapy and avoid the four cycles and use more risk-adapted chemotherapy and make sure people are not getting the fourth cycle and getting standard three cycles of BEP for good-risk disease.

Alicia Morgans: Absolutely. I look forward to seeing the study that you just described. I think that would be a great approach because I do think that we have to take whatever measures we can to really strike that balance between cure, but doing just enough treatment to avoid the morbidity that we certainly cause, though of course, we don't need to. And especially in these men, because they are diagnosed so young, it can be... these are tough conversations to have, particularly in the setting of being overwhelmed by this new cancer diagnosis and all that the treatment entails. So really a reminder to us to continue to have those conversations and ensure the survivorship care that these guys need.

And of course, one comment that you made about mental health and depression being more prevalent in this group than we would have anticipated, at least in terms of identifying suicide as a cause of death in this population, is absolutely something that I think, as a world, as a nation, for sure, we are recognizing is an issue in all of us that we have to be sure to identify and intervene. Is this something that you think deserves more attention perhaps in a survivorship setting for these patients?

Sia Daneshmand: Oh, absolutely. and these organizations are popping up, fortunately, at various institutions. These AYA, the Adult Young Adolescent survivorship places that focus on mental health, focus on support. I think it is absolutely paramount, particularly with a diagnosis. We know the cure rates are high, but for a young man getting a cancer diagnosis, it really is a life-changing event. And it's routine for us to be like, "Oh, you'll be okay," and a 15 minute, 20 minutes, half-hour discussion doesn't quite do it. So I'm really pleased to see more and more of these AYA-type programs popping up. I think it needs to continue. I do see patients five years later, completely cured, and they are still having those late sort of psychological effects of their treatment, even if it's surveillance.

And one of the areas I've been interested in is measuring the anxiety levels with surveillance. There are some validated questionnaires. We did do some prelim work looking at these questionnaires of... and as you can imagine, the anxiety levels go down as the surveillance continues. But again, I think the big picture here is more surveillance for stage one disease where relapse rates are quite high, I'm sorry, quite low, and more surgery in stage two disease where cure rates are quite high, and now on the heels of the SEMS trial that I presented at GU ASCO, this surgery and early metastatic seminoma with an 80% two-year recurrence-free survival, and hopefully we will have long term data for that. Now we're seeing more surgery being performed for stage two seminoma, early-stage two seminomas, and we have a clinical trial design that is in development for all stage two germ cell tumors that will incorporate microRNA 371 into this sort of treatment algorithm.

Alicia Morgans: Well, thank you so much for explaining that and certainly to you and your team for continuing to contribute as we really improve our approaches and hopefully limit our complications related to treatments. This second abstract that you discussed is really from the group at Indiana University, thinking about long-term follow-up and risk of late relapse. Can you tell us a little bit about that?

Sia Daneshmand: So this was a late relapse. Again, it was more of an update. IU has really been a leader along with MSK in delineating the risks of late relapse, and what they are. So this was basically an update. As we know, late relapse is any relapse that occurs after two years after primary treatment, 3% in non-seminoma, and it is 1.4% in seminoma. So it is rare and it ranges widely in terms of when it can present, anywhere from three years to up to 40 years later. I've seen patients 20 years after successful treatment, so it's pretty unpredictable. It's hard to say we need to focus on a particular time period. At least half the patients have symptoms and about half the patients present with tumor markers. So again, going back to the discussion about long-term follow-up for these patients, I think it's easy to educate the patient themselves, wherever they go after 10 years. I'm happy to see them forever. These are easy follow-ups, and I love seeing long-term follow-ups with these patients.

All it takes is a symptom check and tumor markers for a long time. Just add that AFP along with your vitamin B12 levels and whatever else you are checking. So that's an important thing. The other is that teratoma was the most common histology seen. Sarcomas and adenocarcinomas are accompanied by teratomas in up to 25% of the patients, and many of these are chemo resistant. So really surgical treatment and surgical resection of all the recurrent sites is essential. Now if you have not had chemo previously, you are chemo naive, those patients tend to respond a little better as you know. But if you've had chemo any time in the past, it seems that the histologies, the sarcomas, the adenocarcinomas, and the transformed somatic malignancies are going to be a little bit more chemo resistant.

So most of these are surgically resectable. We, as everyone in high-volume centers, recommend that these cases be done at centers of excellence with experience with these types of things. So basically the takeaway from... there are two takeaways, actually. One was that surgery remains the most important modality for treatment for these patients. They had 2,700 patients with 90 late relapses presented, 42 chemo exposed, 48 chemo naive patients. Out of all of these, they had nine with next-gen sequencing, and there were no actionable findings with these nine patients. Tumor mutational burden was also low in all the patients, so we are not there yet to personalize and treat them with specific systemic therapy. So again, more work for us, Alicia.

Alicia Morgans: That's true. But if you guys aren't doing the work, we won't get the tissue to send for sequencing so that when we do have those treatments, we won't have the tissue that we need to identify which treatment we would need. So we love the surgeons, and certainly, with teratoma, I would hope that we are using surgery to take care of that.

Well, thank you so much for presenting or describing the discussion that you gave at ASCO 2021. Certainly, both of these abstracts really deserve our attention, and I think to highlight the long-term need to continue to follow these patients, whether it's to follow them for the complications of the treatments that they've been already given, or whether it is to identify cancer that may be coming back, it's critical that we ensure good communication, good education, and really a connection with these patients over time. I really appreciate your time and your thoughts.

Sia Daneshmand: Thank you so much. It was a pleasure talking to you this morning. Thank you.

Alicia Morgans: Thank you.