← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 128: Testicular Cancer Series, Pt 2 - Stage 1 and 2
Ronak Mistry, Vivek Patel, Dan Hausrath
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Transcript29 lines
- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. Welcome to another episode of the Fellow on Call, the Hemong podcast. We're coming at you from Reload University Medical Center. I'm Ronak.
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B
I'm Vivek.
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C
And I'm Dan.
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A
And in today's episode, we continue on our testicular cancer journey, this time talking all about testicular stages one and two.
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B
I'm really excited to get into this episode. Testicular cancer is one of those amazing advancements in oncology where we've really pushed up the curate in these early stage patients. Really close to that 90 to 100% mark, and that's quite incredible. So it's a really good story and excited to get into the data because this is stuff that is important to know. And remember to use our website as a reference. We're going to actually link to the data behind what you do, not just the guidelines.
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C
Yeah. And your board studying will benefit. So give this one a listen.
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A
That sounds good. Guys. Let's roll that show. Guys, I want to give a full disclosure. We will see how this recording goes. I just had to stop at the dentist office before this recording and the entire right side of my face is numb. I can'. Feel the right side of my chin. But we had a podcast to record and so here I am. I've done this podcast now with a bleeding hand with COVID twice, and I'm sure some other injury along the way. But now I can say that my speech may also be impaired because of some dental work.
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B
I mean, this isn't as bad as Dan recording from France, which we've now banned. Dan is not allowed to record any podcast when he's on vacation, but that was ridiculous. Dan.
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C
Well, I appreciate you guys working with me on that. And Ronick, I'm just honored that you've spent the time here with us and not taken this opportunity to get a face tattoo while your face is still numb.
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A
I did think about it, but I.
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B
Figured maybe that's for when I get.
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A
The left side of my face and I can schedule around our meetup times. Guys, last week we started our conversation on testicular cancer, going through sort of an overview of this disease. And as we sort of highlighted there, testicular cancer management really is one of the success stories of oncology. And so today I'm happy that we're discussing some of the management of stage one and Stage two. I do want to remind our listeners about utilizing our show notes. Our team does a phenomenal job of putting these show notes together and I really think that the testicular cancer show notes with all the graphics and the charts and things that they've put together are really going to help really drive home some important points about the management of this disease. So I'm sure there'll be fantastic show notes for this episode too, so definitely check those out on our website. Well anyway Vivek, do you want to kick us off with the case for this episode?
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B
Yeah, let's do it. So I'm going to really abridge this case. We have a 28 year old male. He had a testicular lump underwent in the scrotal ultrasound that was concerning for testicular cancer with a hypoechoic mass, which is a classic finding. He was then referred to urology. He got baseline serum studies with an afp, beta, HCG and LDH which were all undetectable. One week later he underwent an inguinal orchiectomy with pathology that showed a pure seminoma that measured 2.5 cm and there was no evidence of lymphovascular invasion. Post orchiectomy tumor markers remained undetectable. He underwent staging imaging with a CT chest, abdomen pelvis which was unremarkable. Check out our first episode where we really get into the nitty gritty on the tumor markers and the staging imaging. So this patient has stage one disease given that it's localized without retroperitoneal lymph node involvement. Remember, stage two is retroperitoneal lymph node involvement only and stage three is involvement in other nodal sites or distant sites. So in general this testicular cancer follows the anatomic pattern when it starts to spread. So can one of you go through how you approach a patient with stage one seminoma?
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C
The important thing to know is that long term disease specific survival is nearly 100% for this disease for pure seminoma. So our options include active surveillance with follow up every three months for a year and then spread out after that carboplatin at an area under the curve or AUC of seven for one to two cycles or radiation to the retroperitoneal nodes at 20 gray given over 10 fractions, so two weeks of therapy in total. There were several studies looking at active surveillance given the extremely effective treatment options at disease relapse and one of the largest studies published in the European urology journal in 2016. They looked at all patients with stage one testicular cancer undergoing surveillance between the years of 1984 and 2007 in the Danish Testicular Cancer Database. There are about 2,000 patients identified within that cohort with seminoma. At a median follow up of 15 years, there was a 19% relapse rate. Overall, most of those relapses occurred within the first two years, so 75% of all relapses were within that initial time window. Only 5% of total patients with stage one seminoma relapsed after two years. The median time to relapse was 13 months and again survival in this cohort was nearly 100%. We'll have a link to that study in our show notes as well. Both radiation and chemotherapy were assessed in many studies, but we want to highlight a non inferiority trial comparing these two approaches. There was a cooperative group study run by the EORTC published in the Journal of clinical oncology in 2011. It enrolled patients between 1996 and 2001 and included nearly 1,500 patients in total. They were randomized at the very normal ratio of three to five between carboplatin or one cycle of radiation. Relapse rate at five years was 5% with carboplatin versus 4% with radiation, which met a non inferiority endpoint. The authors stated that carboplatin significantly reduced the risk of contralateral recurrence of testicular cancer with with a hazard ratio of 0.22. Now these findings may seem very impressive, but it's always really important to know what the baseline rate of the event is when you're looking at something like this and when you do look at that, the risk of contralateral relapse is only 0.01%. So this benefit overall is kind of trivial given the extremely low baseline risk. So we'll have a link to that study in our show notes as well, but just keep that in mind when you're looking at numbers like this. There were also some studies that looked at risk factors for relapse in order to try and help establish a risk adapted approach for therapy. Both tumor size and invasion into the retis testis were found to be risk factors that were predictive of relapse in multiple studies. There was a systematic review of these studies published in the European urology journal in 2018. A total of 20 studies were included and a meta analysis could not be done. Unfortunately, given the large amount of heterogeneity between these studies, when evaluating the studies in a systematic Fashion and assessing for bias. The prognostic impact of tumor size and retice testis invasion to guide clinical practice was lacking overall with a high risk for over treatment in patients. In general, we recommend active surveillance as standard of care to prevent long term toxicity from either chemotherapy or radiation, with a concern for over treatment and potential secondary malignancy. If patients are not reliable for follow up or don't want to go forward with active surveillance, either because of anxiety or they just don't want to have all those scans, or whatever the reason may be, it is reasonable to offer either radiation or chemotherapy. But in all cases, remember the disease specific survival is nearly 100%.
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B
You know, it's really important to know stage one seminoma, we have these options, active surveillance, and this is true for stage 1 non seminomonous germ cell tumor as well, which we'll talk about here in a second. So our patient, we discussed the options and he opted for active surveillance and he remained in remission at 5 years of follow up. Let's change the case though. So what if the same patient had non seminomous germ cell tumor? Let's say at baseline the BHCG was mildly elevated, about 200, no other evidence of disease on imaging, and there was normalization of tumor markers post orchiectomy when we waited for those half lives to finish. So how does that approach differ for a stage 1 non seminomatous germ cell tumor patient?
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A
So whenever you have a patient with stage one non seminoma, it's really critical to know if they had normalization of their tumor markers post orchiectomy. So remember that we track these tumor markers to the nadir based on the half life of beta HCG at a day or so and afp, which is about a week. If the tumor markers have not normalized or they start to rise, it's really important to repeat staging imaging. And if there's still no evidence of disease, then we treat the patient as if they had disseminated disease with chemotherapy. And we would characterize this as stage 1s. And we sort of discussed this a little bit in our intro episode just last week. Let's say in this case we had resolution of tumor markers and we had a localized non seminoma. So what are our treatment options there? Well, they are active surveillance. You can give chemotherapy with bleomycin, atoposide and cisplatin, a regimen called bep. For one cycle, you can undergo a surgical retroperitoneal lymph node dissection that is typically abbreviated RPLND in the literature. Once again, there's no difference in survival when you're comparing these approaches. In that same Danish registry study that we mentioned earlier for the seminoma and Dan brought this up just moments ago, outcomes for active surveillance were assessed for non seminomas as well. What they found was that There were nearly 1400 patients with non seminomatous testicular cancer that were included in this study and the median follow up time was 15 years. And the relapse rate was 30% on active surveillance, which is about 10% absolute points higher than a seminoma. For active surveillance, the 10 year disease specific survival was 96%. So again, very, very, very favorable outcomes and patients were salvaged with either chemotherapy or surgical rplnd. There are multiple studies defining the chemotherapy regimen which ultimately stands to this day as bep. And surgical advances showed promising results for rplnd. This led to a randomized phase three trial run by a German cooperative group that was published in the JCO in 2008. And so what they did was from 1996 to 2005 there were nearly 400 patients that were randomized to either BEP X1 or RPLND. The two year recurrence free survival was 99% in the chemotherapy arm versus 92% in the surgery arm. So an overall reduction by 7% absolute points. This established superiority of chemotherapy to prevent recurrence, but there was no difference in overall survival that's so important. So yes, maybe there was more recurrence but no difference in overall survival. There was a concern for late effects of chemotherapy, including the risk of secondary hematologic malignancies, pulmonary toxicity, which is a big deal with the bumycin neuropathy and potential cardiac side effects. And for RPL and D, one of the major concerns is the risk of ejaculatory dysfunction occurring in about 10% of patients and that there is still roughly 10% of patients who will still need chemotherapy regardless. So some risk factors for relapse include predominant embryonal component and that's defined as more than 50% and or lymphovascular invasion. But these are not recommended as reasons to change a management plan given overall low level of evidence of predictive impact. So for these reasons, active surveillance is once again really a very reasonable option to offer our patients and quite frankly the preferred strategy for most patients who can follow up reliably. So to recap some really important points that we just mentioned, so same overall survival with any of these approaches with active surveillance, a little over one in four patients will relapse requiring chemotherapy. So 75% never actually needed therapy. And this is the preferred approach for patients who can follow up reliably. In patients that undergo RPL and D, about 1 in 10 patients will relapse and may need chemotherapy, or in that case will need chemotherapy. And with chemotherapy for one cycle, only 1 in 100 patients will relapse and and require more chemotherapy treatment. But everybody gets chemotherapy. So go back and listen to this because this is such an important conversation when you're presenting your patients with options. Doing active surveillance sometimes scares people because we're doing nothing, but in reality we are doing something. And it's our job as their oncologists to sort of explain everything to them. Chemotherapy is not without its fair share of toxicities, especially not with bleomycin. So if I can change this case, We've talked about seminomas here, some non seminomas without any evidence of tumor based on tumor markers. If we change this case, and if our patient had no AFP or beta ACG elevation at initial evaluation and pathology after the inguinal orchiectomy showed a pure seminoma, he underwent a CT chest abdomen, pelvis, which did show a evidence of an enlarged retroperitoneal lymph node measuring 2.5 cm and 2 cm, respectively. There was no evidence of pulmonary metastasis and post orchiectomy tumor markers remained undetectable. So remember that retroperitoneal lymph node involvement only is characterized as stage two disease. So how do we go about treating stage two disease?
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B
So if you remember the number two for stage two disease and testicular cancer, you'll be good to go because for any testicular cancer patient with a lymph node greater than 2cm, you're going to be thinking about chemotherapy. And so that's just an important concept, whether this is seminoma or non seminoma. The other thing that we have mentioned, so as you noticed, for seminoma, you didn't hear the RPLND as options. For stage one seminoma, it was active surveillance, carboplatin for one to two cycles or radiation. So seminoma, unlike non seminoma, you think radiation instead of rplnd. And the way I remember that is, you know, the imaging machine, the Siemens company. If I just remember Siemens and I picture Siemens, that reminds me of seminoma. For some reason, it just sounds similar. So I just remember that as radiation for seminoma, whereas when you have non seminoma, you don't really think about radiation as much, and this is true for stage two seminoma as well. For lymph nodes less than 2cm, both radiation and chemotherapy are treatment options. For lymph nodes greater than 2 cm, chemotherapy is required and again, we're talking about retroperitoneal lymph node involvement only. And for seminoma we don't have tumor markers. We're not thinking about the tumor marker question. Chemotherapy is given as something called bep bleomycin plus etoposide plus cisplatin as Ronick had mentioned, for three cycles given every three weeks or alternatively a regimen without bleomycin called episode etoposide plus cisplatin given for four cycles. I'll note that cisplatin was found to be superior to carboplatin similar to lung cancer in a randomized study that we'll link to our show notes published in JCO 1993 if you're interested. And that's why you're not seeing carboplatin but seeing honestly the harder to tolerate more toxic cisplatin. But again, generally we're thinking of a younger patient who could easily take cisplatin based therapy. We think about radiation. This is a total of 30 grays, so it's given over a few weeks. There was a pivotal meta analysis that led to chemotherapy being the preferred agent for patients with nodes greater than 2cm, and this was published in the Annals of Oncology in 2015. It included 13 studies of which four were prospective. There was no difference in relapse rates for nodes less than 2 centimeters when you're thinking about chemotherapy versus radiation. However, there was improved relapse rate favoring chemotherapy for nodes greater than 2 centimeters at 5% with chemotherapy compared to 12% with radiation. So you're having a 7% absolute benefit when you think about chemotherapy for those lymph nodes that are greater than 2 cm. When thinking about the incidence of secondary malignancy, this was 4% with radiation. We're often thinking sarcomas very difficult to treat malignancies related to radiation and 2% with chemotherapy. Again, we also think about the heme malignancies for both of these as well. We'll point out that there was a recent single arm phase two study called the CEMS trial that was published in JCO 2023 looking at the role of RPLND in stage two seminoma, something that we didn't historically do. SEMs stands for surgery in early metastatic seminoma SEMs. They included single arm 55 patients with isolated retroperitoneal adenopathy measuring 1-3 cm. So overall low burden of disease, median follow up was about three years. The two year recurrence rate was 22%. And all patients were successfully salvaged with chemotherapy. This showed that RPLND can be used to cure about 80% of patients with low volume retroperitoneal nodal involvement of seminoma. So it'll be interesting to see how this is incorporated in the future. But ultimately, remember, we're talking about relapse rates at 5%, 12% much lower when we're thinking about either a radiation approach or a chemotherapy approach. We could spare that 4% secondary malignancy risk, the 2% secondary malignancy risk with the potential surgery. But this is not primetime. It's an interesting study that was published very recently. We'll have an episode with our urology expert that we can talk about how this might be incorporated in the future management for these patients. So in this case, our patient got chemotherapy given that they had lymph nodes greater than 2 cm with BEP times 3 cycles. And he primarily chose this because he could be done with therapy sooner rather than EP times four cycles. He'd rather just be done with it. And he wanted to minimize the risk of neuropathy with further cisplatin use. Remember that if the nodes were less than 2 cm, we could choose either chemotherapy or radiation. Again, 2 cm as the cutoff for requiring chemotherapy. Let's take the same case. What if the same patient had non seminominous germ cell tumor? And remember, we have two RP nodes involved measuring 2.5 centimeters and 2 centimeters, respectively. And let's say that the tumor markers had normalized after orchiectomy.
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C
All right. Well, it's important to always remember that if the tumor markers do not normalize, then the patient will require chemotherapy. And that treatment algorithm will be discussed in our next episode. For patients with Stage 2 Non Seminomatous Testicular cancer and a normalization of tumor markers, the options are retroperitoneal lymph node dissection or chemotherapy, depending on the number of nodes involved and the size of those nodes. Radiation is never really an option. In non seminoma, the cutoff of 2 cm for stage 2 still applies. If there's any node greater than 2 cm, then the patient requires chemotherapy with BEP for 3 cycles or EP for 4. That's just a whole separate treatment algorithm here. Also, if more than five nodes are involved, in other words, just a lot of nodes, then we have to go down that same pathway of chemotherapy with BEP for three or EP for four. For patients with nodes less than 2 cm, an RPLND is going to be the preferred approach, but chemotherapy can be considered as well, depending on what the patient's preference is. The data behind this is actually pretty interesting and requires a little historical interlude. If I can steal that thunder from what VIVEC normally talks about here, RPLND was the standard of care for these patients dating back to the 1970s. There was a study published in 1984 that looked at the benefit of adjuvant chemotherapy with cisplatin, vinblastine and etoposide. Ultimately, it was found that patients could successfully be salvaged with chemotherapy at the time of relapse rather than giving adjuvant chemotherapy to all patients. This improved the rate of over treatment. With chemotherapy with relatively low risk surgical procedures and high cure rates. We'll have a link to that study in our show notes and subsequent studies showed that less chemotherapy could be given adjuvantly for these patients, sparing them from bleomycin and all the attendant toxicities with that agent. The NCCN guidelines recommend adjuvant chemotherapy based on final pathologic node evaluation after RPLND. If all nodes are less than 2cm and 5 or fewer are involved, then surveillance is preferred. With a relapse rate of roughly 20%, that's considered N1 disease. If there's any node greater than 2 cm or more than 5 involved, then you go forward with EP for two cycles. But surveillance would also be an option. There's still a roughly 50% relapse rate based on historical studies in patients who were just Observed, that's considered N2 disease. So any node greater than 2 cm or more than 5 nodes involved. If any node is greater than 5 cm, so N3 disease, then BEP times 3 or EP times 4 is the preferred regimen.
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B
One of the interesting things there is you mentioned that if there's a node between 2 and 5 centimeters that the relapse rate is 50%. And when we looked at these studies from the fellow on call, we found that the staging actually changed that in those historical studies, N2 disease could include lymph nodes up to 10 centimeters. That's a totally different patient that we would now categorize as N3 disease. So Ronak, has there been any recent studies that have looked at this idea? Because we've been Talking about BEP times 3 cycles or EP times 4 cycles, then randomly for N2 disease and non seminoma we have this random EP times 2 cycles. It wasn't randomized. This is just sort of some studies that show that these outcomes are pretty reasonable with this historically high relapse rate. Has anybody looked at this in the modern era?
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A
They have actually. And so the University of Indiana has a prospective database for all patients treated with testicular cancer. And so they actually looked at adjuvant chemotherapy outcomes for non seminomatous stage 2 patients with the results that were published in the JCO in 2022. And what they found were there were no differences in relapse free survival with or without adjuvant chemotherapy for N1 and N2 patients. So in total, 97 patients were included and there were 46 patients with pathologic N2 disease. The five year relapse free survival was roughly 85%, suggesting that this patient population should be considered for active surveillance as opposed to EP times two as they can be successfully salvaged with chemotherapy. And so this is an example of an excellent study because there has been no randomized studies looking at EP times two versus surveillance. And the cohort had data prospectively collected which made for a great publication. And we'll link that in our show notes as well.
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B
Now we've really set the stage and I want to recap. Stage 2 Non Seminoma Germ cell tumor. Remember, we don't think about radiation for non seminoma. The Siemens machine that you think about, that's radiation for seminoma. For non seminoma, radiation is not an option. So we have RPLND for less than 2 cm. If the patient has a node greater than 2 cm, we think about chemo instead of RPLND. And then when we think about the pathologic stage after we do the RPLND, it's really only for patients with nodes greater than 5cm that we must do chemotherapy. There's a gray area if they're between 2-5 cm where we have this EP times two cycles. Again, the University of Indiana has that great study suggesting that, hey, maybe we should reconsider that. But the NCCN guidelines do say that chemotherapy with EP times two cycles is a preferred management option. And the last thing that we want to finish out this episode with for these patients, if they had chemotherapy treatment for the stage two disease and they have any tumor that's left over for non seminoma, these lesions must all be resected. There's a breakdown in these residual tumors that will either be leftover testicular cancer, which is not the most common thing, benign Lymph nodes, potentially teratoma. We see that some of these patients have teratoma, which are both radiation and chemotherapy resistant. So some patients will have residual teratoma and so resecting all residual lesions and non seminomatous germ cell tumor is critically important.
- [24:35]
A
That was a fantastic recap and discussion about treatment for Testicular Stage 1 and 2 disease. Listeners, make sure you guys go back through this discussion. Check out our show notes. This is really, really, really important information, not only because it comes up on board exams, but because we can cure our patients with testicular cancer. But for what it's worth, you can see how different nuances, the exact same question, they can just change the type of pathology from seminoma to non seminoma. And magically the question is a different question. And so you can see how easy it is to write a test question, which is why these questions end up so frequently on our interning exams and our board ex. Again, it's a success story, but also highly testable because it's easy to write questions, but also because it's very curable and they really want you to know stuff about it. Guys, any final thoughts that you all have?
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C
No. I think that was a great summary and great episode. Just remember, these folks are very curable. The name of the game in a lot of cases because of those high cure rates is trying to spare people the effects of therapy.
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B
The other thing that I have to say is that when we think about looking at guidelines, the EP times two cycle seems like we have to do that on everybody. You always need to look at the data. And we hope that our show will provide a framework for everybody in the future to say, hey, this is actually what the study shows. Why is surveillance a potential option for these patients? And you can see there's a great study at University of Indiana, one of the highest centers with Dr. Einhorn there, one of really the pioneers of treatment in testicular cancer where they're not doing that. So check out our show notes. Check out that part in particular, because it's the one thing that I think is going to actually have an impact on the patient in front of you. And you think about neuropathy related to cisplatin. Platinum agents do increase the risk of cardiovascular toxicity. Etoposide. These are not easy treatments. And so we should really, really think about whether our patient needs these treatments or if we're just over treating them.
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A
And just to further hit that point home, remember the demographic of patients getting a lot of these diseases, they're often younger patients. And so they have a long life ahead of them to live where the effects of chemotherapy may take root either at that age or later down the line. So definitely don't want to be utilizing chemotherapy if you don't have to.
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B
All right, guys.
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A
Well, that wraps up another fantastic episode of the fellow on call. So until next time, we'll see you all later.
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B
See you later.
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C
Peace.