This interview in honor of Testicular Cancer Awareness Month features Dr. Aditya Bagrodia, an Associate Professor of Urology at the University of California, San Diego. Dr. Bagrodia explains the factors that should be considered when selecting treatment options—including surgery, chemotherapy, radiation, or surveillance—for patients with testicular cancer, the future of recent advances such as cancer detection with microRNA, and the importance of taking a multidisciplinary approach to ensure the best possible outcomes for patients with this disease. 

This interview has been conducted in partnership with the American Urological Association, a premier urologic association, providing invaluable support to the urologic community. Their mission is to promote the highest standards of urological clinical care through education, research, and the formulation of health care policy.

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today we're here for a discussion in honor of testicular cancer awareness month. I'm joined by Dr. Aditya Bagrodia, who is an Associate Professor in the Department of Urology at UC San Diego Health System. Dr. Bagrodia, thank you so much for joining us today.

Aditya Bagrodia, MD: My name is Aditya Bagrodia. I'm a urologic oncologist at the University of California, San Diego. I treat patients with all urologic malignancies. I have a lab that studies markers of minimal residual disease, tumor heterogeneity in evolution, and cisplatin resistance in testicular cancer patients.

Oncology Data Advisor: So what factors do you consider when determining whether a patient with testicular cancer should receive treatment or surgery?

Dr. Bagrodia: It's a great question, and I think first things first, it's absolutely mandatory to get complete and comprehensive staging. If you have a patient that comes in with a suspicious mass, it's incumbent to get serum tumor markers and an ultrasound as an initial part of the diagnosis. Typically, it's going to be imaging of the chest, abdomen, and pelvis. I prefer a computed tomography (CT) scan of the chest, abdomen, and pelvis.

Then if they've got advanced disease with widespread metastases, typically that's going to be chemotherapy as the upfront management option. If they've got no evidence of metastases, it's really imperative to follow the tumor markers after the orchiectomy to make sure they normalize; to look at the risk factors for recurrence based on certain pathologic features, including the presence or absence of lymphovascular invasion or embryonal carcinoma in the primary; and to understand the patient preferences with respect to minimizing the chances of recurrence with any type of active intervention, versus trying to avoid any further therapy with going on a surveillance program.

What I think is imperative is that all of these options are actually offered to the patient and that every case is reviewed in a multidisciplinary tumor board. Let's say that you have a patient, and if they're stage I, I think surveillance is generally going to be considered the preferred option, if you will. There are, of course, patient-specific characteristics. If they've got, say, malignant transformation in the primary retroperitoneal, lymph node dissection may be a good option that's actually endorsed by the American Urological Association. There's no real comment on it from the European Association of Urology.

For instance, if they've got stage III metastatic disease, now we're typically going to talk about chemotherapy and the option for surgery, retroperitoneal lymph node dissection, which is removal of all the lymph nodes in the retroperitoneum, where testis cancer tends to spread. The testes actually begin up at the level of kidneys. They descend into the scrotum shortly before we are born, and about 90% of testis cancers follow a path of spread right along that area where the testicles descend. It allows us to actually offer local regional treatments such as retroperitoneal lymph node dissection (RPLD) or radiation therapy, even when patients have metastases to the retroperitoneum. If it's a non-seminoma germ cell tumor patient, which is about half of the cases, and they've got stage II disease—which is going to be evidence of cancer cells in the retroperitoneum—surgery is one of the options.

Now, first off, I think it's important to understand why surgery may be a part of our armamentarium, and there are several things to consider. First of all, I think it's important to note if this is a retroperitoneal lymph node that was present at the time of diagnosis or if this is a retroperitoneal lymph node that actually developed over the course of surveillance. There aren't a lot of data behind this, but if it's a node that developed over the course of surveillance, we have some natural history to indicate that they haven't developed widespread metastases, so surgery could be attractive in that setting. Again, I think a multidisciplinary approach where you have the radiologist, pathologist, medical oncologist, urologist, and radiation oncologist discussing these cases is also imperative.

Now, let's say they've got retroperitoneal disease. If we jump in there, especially in somebody who was newly diagnosed, and did a retroperitoneal lymph node dissection, actually in about 20% to 30% of the patients, we're going to find no cancer. So the good news is no cancer. The bad news is you went through fairly significant surgery to kind of ascertain whether you have cancer or not. In the primary tumor, if it's pure teratoma and there's malignant transformation, then retroperitoneal lymph node dissection is often more attractive because those particular histologies are resistant to chemotherapy.

Then, when you actually look at the nodes, there are several features that are important. One is how many; one to two nodes will probably be a clinical scenario where surgery is more attractive. Once you get beyond three to five, you really have to worry about cancer cells being not only in the retroperitoneum, but other parts of the body, as well. The number of nodes is important, and so is the size of the nodes. Of course, there are nuances to this once you get beyond about 3 cm. These are just general guidelines for the likelihood of having a curative intervention for a patient with pathological N2 disease, is likely going to be somewhat low.

Then of course, it's important to take into account the patient's desires and preferences. There are pros with surgery, including avoiding some of the long-term side effects of chemotherapy, such as early-onset heart disease and development of secondary cancers, that may be attractive with surgery. On the flip side, there is a small—albeit real—increased chance of having recurrence if you undergo surgery, since we are just treating one area of the body, as opposed to chemotherapy, which obviously goes throughout the body. For the sake of completeness, historically in seminoma, if you've got stage II disease, the options are chemotherapy and radiation therapy, which are both highly effective. That's the good news. But again, we see these long-term potential side effects of nerve damage, secondary cancers, heart disease, and injury to the kidneys.

Recently, retroperitoneal lymph node dissection has received renewed interest in the management of patient with stage II seminoma from two large clinical studies, one out of Europe and one from the United States. We were happy to participate with the fourth-highest contributing institution. It showed, in patients with retroperitoneal disease of less than 3 cm, with no more than two nodes, that the likelihood of being cured with surgery alone was excellent and the need for additional therapy was quite low. I think in the upcoming years, we're actually going to see an uptake in surgery for patients with seminoma, as well, with the idea of potentially avoiding the long-term toxicities of chemotherapy or radiation.

Oncology Data Advisor: That was a really great overview. So what are the situations where you consider watching and waiting before initiating treatment?

Dr. Bagrodia: It's a great question. First off, I would say that generally when it comes to testis cancer management, nearly always it's preferred to get the diagnosis right and to be deliberate instead of hastily jumping into any type of intervention. To start with, I oftentimes see patients with what we call indeterminate scrotal masses. These are generally non-palpable. Maybe they had an ultrasound for some testicular pain or as a part of an infertility evaluation, and something abnormal was identified. Now, in that scenario, if the serum tumor markers are negative, there is nearly certainly no urgency to jump in and do anything invasive.

Our American Urological Association guidelines indicate that repeat imaging in six to eight weeks with an ultrasound to see if this thing is growing, if it's changing, or if it's developing features that are consistent with cancer is perfectly reasonable, and that's what I do in my clinical practice. The small indeterminate testicular mass before the diagnosis of a cancer is a scenario where I think it's okay to wait. There are others that advocate for actually going in, surgically removing the area of concern, and also taking biopsies, with the idea being that if a tumor was identified, you would go ahead and remove the remainder of the testicle. But if there's no tumor identified and no evidence of any precancerous lesions on the biopsy, that can actually be replaced back into the scrotum. There's never been a study, and likely never will be, of keeping an eye on things with an ultrasound versus nucleating it, but I think the bottom line is we don't need to be rushing in to do any removal of the testis at that time.

The second clinical scenario, where I think it's quite important to be a little bit more deliberate, is in patients with stage II disease. These are in patients that, as I mentioned earlier, have evidence of a retroperitoneal lymph node or lymph nodes. Again, if you go in and jump to doing an operation, in about 20% to 30% of those patients, there's going to be no cancer identified. What I do in my clinical practice if surgery or chemotherapy or radiation are indicated, before jumping in and treating the patient, I will repeat imaging from top to bottom, as well as tumor markers, chest/abdomen/pelvis CT, and serum tumor markers. If that node has gone away, then you're feeling pretty good to maintain yourself on a surveillance program.

If you've developed metastases, then of course we're going to be treating with chemotherapy. If that node's just a little bit bigger and it's remaining consistent with a testicular cancer metastasis, that's the patient that's likely going to benefit from a locoregional treatment such as retroperitoneal lymph node dissection or radiation, which is still sometimes offered. That small-volume stage II disease is another important aspect of watching and waiting.

Then finally, in patients that have received chemotherapy and they've had a good serum tumor marker response and a lot of their disease has melted away, we sometimes see what are called residual masses. It's pretty consistent across guidelines that if those masses are greater than about 1 cm, the standard of care is to go in and surgically remove them. Typically, that's a post-chemotherapy retroperitoneal lymph node dissection. But if they are less than 1 cm or right at about 1 cm, in those cases, I'll often embark an early period of surveillance where we repeat imaging, for instance, in three months. If it's continuing to shrink or if it's staying stable and certainly if it's not growing, then you can fairly confidently remain on a surveillance program, but it is imperative that the patients are reliable and have been thoroughly explained how important it is to continue to follow things.

Oncology Data Advisor: So, of the new approaches that are currently in development for testicular cancer, which do you think are going to be the most promising?

Dr. Bagrodia: It's an excellent question, and if I had to hypothesize about what the next major game changer in testicular cancer will be, it's microRNAs These are non-coding RNAs that are measurable in the blood. Suffice it to say, that they have excellent sensitivity and specificity for the diagnosis and prediction of whether cancer cells are present or absent. Walking through the disease spectrum, if a new patient comes in with a suspicious mass, currently the standard of care is to get tumor markers and an ultrasound. I think we'll see in the next several years that a microRNA test before removal of the testis will be able to tell us with excellent, excellent sensitivity and specificity if a cancer cell is likely to be present or not. These are blood tests, and they're in development. Our lab's done a lot of work on microRNAs. Before testis removal, they're very, very good at predicting.

In patients that have had their testicle removed without any evidence of metastases, there's a lot of promise that microRNAs can help predict who's likely to have small or cold metastases that may benefit from additional treatment and who is likely to have been cured with removal of their testicle alone and can be safely watched. As we get into more advanced stages of disease, microRNAs are highly diagnostic, and they may provide some information on who's responding to chemotherapy who could potentially have treatment deescalated with less cycles, or who may not be responding and needs to go on to more intensive treatments potentially. That's what's captured the attention and excitement of the germ cell tumor community, both domestically in the United States and internationally, as well. There are several ongoing clinical trials along the lines of microRNAs.

Fortunately, the majority of patients with testicular cancer are cured with some combination of chemotherapy, retroperitoneal lymph node dissection, surgery, or radiation. However, about 10% to 15% will have disease that's refractory. Despite our best efforts of newer interventions, including immunotherapy trials—which have largely been unsuccessful—and targeted therapy trials which are ongoing but haven't really been game changers, the bulk of the resources are currently trying to identify early on who's likely to have really bad multiply-refractory disease. How can we identify it early, intensify treatment earlier, and preclude them from getting to a point where they have a more dangerous tumor?

Oncology Data Advisor: To wrap up, do you have any words of advice for members of the cancer care team who are treating and managing patients with testicular cancer?

Dr. Bagrodia: I do, I do. I think it's always important to remember that these are young cancer survivors that must contend with the treatment-related effects for the rest of their lives. It's absolutely incumbent upon us to be deliberate and get the diagnosis perfectly correct and offer them the perfect care. There's actually a lot of data that suggests that this type of care is offered at expert and experienced centers of excellence, where you see a large volume of testis cancer. There are only about 9,000 cases in the US annually. If you don't have familiarity with this disease, we really have an opportunity to not just help patients, but potentially hurt them if you don't really have a comprehensive understanding of the disease.

I would just say that if this is something you don't see often in your center, consult centers with experience and expertise across the germ cell tumor and testis cancer world. I certainly love receiving consults; I receive them all the time to offer my advice. I think it's absolutely critical to review all new cases in multidisciplinary teams. There's plenty of data that suggests that this is associated with best outcomes. Finally, use all available options. Many times, there are multiple options—chemotherapy, radiation, surgery—and they should be offered to the patients, taking into account the patient's preferences, as well. They should be available in a high-quality format. I can certainly attest that when it comes to retroperitoneal lymph node dissection and testis cancer surgery, you want to have a surgeon that sees a lot of patients, does a lot of these operations, and is familiar with the nuances.

Oncology Data Advisor: Thank you so much for sharing all this valuable information with us today.

About Dr. Bagrodia

Aditya Bagrodia, MD, FACS, is an Associate Professor of Urology and the Genitourinary Cancer Disease Team Co-Leader at the University of California, San Diego. He specializes in the prevention, detection, and treatment of genitourinary malignancies, including testicular, renal, bladder and prostate cancers, as well as in minimally invasive surgical approaches. Dr. Bagrodia has authored or coauthored over 150 publications in peer-reviewed journals. He is a member of several professional organizations, including the American Urological Association.

For More Information

Singla N, Lafin JT & Bagrodia A (2019). MicroRNAs: turning the tide in testicular cancer. Eur Urol, 76(5):541-542. DOI:10.1016/j.eururo.2019.06.010

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.