← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 129: Testicular Cancer Series, Pt 3 - Disseminated and relapsed/refractory disease
Ronak Mistry, Vivek Patel, Dan Hausrath
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Transcript38 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 Merlot University Medical Center. I'm Roanoke.
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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 talk all about disseminated testicular cancer. Just moving on our testicular cancer journey again. This has been a great series talking about a disease with really, really high cure rates. So an exciting topic to talk about for sure.
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B
I never thought that I would be in a solid tumor topic talking about stem cell transplant, but here we are. So excited to get into this one.
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C
Yeah, let's do it.
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A
All right, guys, without further ado, let's roll that show.
- [00:54]
C
So I will go ahead and take charge today. I'm going to start us off by thanking Vivek. Thank you for covering for me this weekend.
- [01:01]
B
Yeah, man. You know, you got to your wine class, covered a consult service for you. You had covered me for a trip to Santa Cruz earlier this year, so I definitely owed you the favor.
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C
Well, I do appreciate it. Southeast beverage education. Big shout out. It was a great time. I think we tasted 42 wines, something like that.
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A
What did you take away from that, Dan? And what kind of wisdom can you impart on us?
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C
Well, I took away an awful lot. I think first and foremost that even when you spit the wine out, I feel like some alcohol gets absorbed from the mucus membranes. Because by like wine number 20, I was like, oh, definitely feel something. And yeah, we tasted some great wines. I told Vivek that I'd get him a bottle of the best wine we tasted, which ended up. It's going to end up costing me a little bit more than I expected it to, but that's fine. He deserves it.
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A
Wow, Vivek, that's amazing.
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B
I'm rolling in here, I win the game. I'm just covering a favor, but I'm getting a bottle of wine. I mean, I'm not going to argue.
- [01:56]
A
All I'm going to say is I think that the next time Dan covers Vivek, I think Vivek owes Dan the local liquor, wherever it is that he travels. I think we should just.
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B
I'm just throw that out there, Dan, I'm gonna get you some nice bourbon. That'll be the repay there. You know, that's it's only fair. It's only fair.
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C
Yeah.
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A
All right, well, that sounds fantastic. And I am very jealous, Dan. I'm gonna have to check that place out the next time I'm in Nashville. But guys, today we are just continuing on our testicular cancer journey, talking about disseminated testicular cancer. And then in the next few episodes, I'm excited that we'll have some guests joining us as well to because as we've been highlighting, a lot of management is multidisciplinary for the management of testicular cancer. And as any of our listeners have been with us for a while know, it's always nice to get insight into what's going on in our colleagues brains when they're helping us figure out our approach to a case. So speaking of cases, why don't we kick off our discussion today with a case?
- [02:56]
B
All right, so we have a 28 year old male. He came in, he ended up getting a diagnosis of testicular cancer. After an ultrasound done by his primary care provider referred to urology. They obtained baseline labs with an AFP that was elevated at 2200, a beta 8 CG that was elevated at 15,000 and an LDH that was three times the upper limit of normal. One week later he underwent inguinal orchiectomy with pathology showing a mixed non semenovatous germ cell tumor with predominant choriocarcinoma. Staging CT, chest, abdomen, pelvis showed four lung metastases all measuring less than 2 cm as well as some scattered retroperitoneal lymphadenopathy. Post orchiectomy tumor markers initially downtrended because remember we looked for the nadir but started rising eventually. With an AFP at 500 and Beta HCG at 6000, the patient has intermediate risk disseminated non Seminole germ cell tumor. We've previously discussed that we risk stratify patients into favorable, intermediate and poor risk for disseminated disease. And that guides our chemotherapy length and choice of regimens. So before we get into all the nitty gritty details on how to treat these patients, can one of you go through the data on this risk stratification system?
- [04:10]
C
Sure. So remember, the first step is are we dealing with seminoma or are we dealing with non seminoma? After that we can stage the patients with isolated disease as stage one, retroperitoneal nodes only as stage two and any other cyto disease as stage three. And beyond that, we use the localization of the tumor and post orchiectomy nadir of the tumor Markers like you were saying to stratify patients as favorable, intermediate or poor risk. This system was developed by the International Germ Cell Cancer Collaborative group named igccg. At a certain point, an acronym becomes less useful when you just keep adding letters and it was published in JCO in 1997. This was one of the most important retrospective studies in testicular cancer. They looked at survival outcomes over 5,000 patients treated between 1975 and 1990 in this database, the IGCCG database, and identified statistically significant prognostic clinical factors. There were several different models of varying complexity tested and they chose a practical model that could be implemented on an international scale, including histology, again, seminoma or non seminoma, nadir of postarchiectomy tumor markers, and location of metastatic disease sites. This practical model was just as good at discriminating prognostic subgroups as those with more and more complex variables included. The risk stratification was then validated using patient level data from three different prospective clinical trials. You can check out the paper, we'll have a link in our show notes and definitely take a look at figures one and two which show those different groups by tumor marker and location. There really is a striking difference in survival with poor outcomes for the primary mediastinal germ cell tumor location and for non pulmonary visceral metastases. That kind of sets those folks apart as having a more aggressive disease biology. There was then an updated prognostic System published in 2021 again in JCO using modern patient data which validated this risk stratification but provided a little bit more accurate estimation of survival. We'll link that study in our show notes as well. For seminoma we generally don't see a tumor marker elevation and there's actually only favorable or intermediate risk because overall this disease is an excellent prognosis. Intermediate risk is defined as any metastasis, so any metastatic disease outside of the retroperitoneal nose or lungs. Favorable risk is everything else. So isolated disease, RP node involvement and or lung involvement all can be considered favorable. Remember that pelvic lymph node involvement with an inguinal node would be higher risk given that these germ cell tumors should follow the anatomic lymphatic drainage system that we discussed previously and really should only be draining to the retroperitoneal nodes. So those inguinal nodes, although they seem like they would be close by, that's more distance spread. For non seminoma we use that nadir value of AFP beta HCG and LDH to help us risk stratify as well as the location. Because remember, in non seminoma, that's where we're seeing these tumor markers be elevated. I always remember this with mnemonic 1.5 and 1.5. We talked about this in our last episode. Intermediate risk is AFP Greater than 1000, beta HCG Greater than 5000, or LDH one and a half times the upper limit of normal. Poor risk is AFP Greater than 10,000, beta HDG Greater than 50,000, or LDH Greater than 10 times the upper limit of normal. Really though, intermediate and poor risk are treated the same. So if you remember 1, 5 and 1.5 for AFP greater than 1000, beta Hg greater than 5000 and LDH greater than 1.5, the upper limit of normal. That's really all you need to know if you were going to take a test on this and how to manage it. For non seminoma, primary mediastinal germ cell tumor and non pulmonary vessel metastases are again, both considered poor risk on the basis of that data we talked about earlier.
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B
So our patient has non seminoma pulmonary mets and post orchiectomy nadir of the Beta 8CG was above 5,000, so they'd be categorized as intermediate risk. We want to reiterate that it's important to establish the nadir of the tumor markers because imagine if those continue to decline, pushing the patient into favorable risk, and then we could treat this patient with less chemotherapy. And that's critically important to wait for that nadir that we've talked about with the half life of beta HCG and AFP differing. So check out our earlier episode on that. Given that we had a beta HCG above 5000, he underwent a brain MRI, which was negative for metastatic disease. Remember that we get brain MRI if the patient has obvious symptoms. Beta HCG greater than 5,000 or just extensive metastatic disease, for example, just extensive lung involvement. Our patient now comes to clinic and is anxious to hear about treatment options. We're planning on BEP times four cycles. So, Ronak, your turn to do one of these historical interludes. How did we get to this BEP regimen?
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A
I feel like we're playing musical chairs today. Everyone gets to try something different that they're not usually doing. So it's my turn to wear the historian hat. So it's time for one of our historical interludes. And so this time we'll talk a little bit about why favorable wrist disease is treated differently than Intermediate and poor wrist disease. So there was a regimen of cisplatin, vinblastine and bleomycin called PVB, which was given for 12 weeks, followed by vinblastine maintenance to complete two years. And this was developed by Indiana University in 1974. And they had roughly a 60% cure rate, which was significantly higher than the historical standard at the time. And so over the years, there were several prospective studies to optimize dosing with reduction in vinblastine. And a randomized study showed no benefit of maintenance therapy for patients who relapsed. The salvage regimen of cisplatin plus VP16, which is also now known as etoposide, led to durable CRs in 25% of patients that were refractory to PVP. The thought was, why not incorporate etoposide and cisplatin in the upfront treatment? And we see this all the time. Right. Something works well in the second line. Let's see if we can move it up in sequence and see if we can improve outcomes. There was then a randomized study from 1981 to 1984 that compared cisplatin and vinblastine plus bleomycin, that PVB regimen to cisplatin plus VP16 or etoposide plus bleomycin. So this is now known as a present day bep. And what they found was that BEP had the same outcomes with a statistically significant reduction in myalgia and peripheral neuropathy. And so this led to BEP given every 21 days for four cycles, that is 12 weeks, becoming the standard of care for treatment of disseminated germ cell tumors. A pretty cool story.
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B
Yeah, it's a great story. And Ronak, can you tell us about how often these drugs are actually given?
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A
Yeah. So the bleomycin is going to be given weekly. The etoposide and the cisplatin is then given daily on days one through five, and that's repeated every 21 days. And so, you know, I think if you're doing the math and you're thinking about this, that's a lot of infusion appointments, especially for younger patients. But at the end of the day, there are very high cure rates. So a lot of encouragement is definitely appropriate in these situations, especially when it gets cumbersome to come to clinic so often.
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C
Okay. For all patients who are intermediate to poor risk, we give this regimen for four cycles. I've also seen VIP for four cycles. Can you explain what that is and kind of where it came from how we got that regimen.
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B
Yeah. So I'll continue on our historical background here. And this is really important to understand this. I will say that the VIP regimen we should not give to VIPs. It's actually not that good in many cases. There is one case where it is something that's preferred and we'll talk about that. So ifosfamide had been shown to have excellent single agent activity and could produce cure in the salvage setting when combined with cisplatin. In roughly 25 to 35% of patients, there was this concern for the hemorrhagic cystitis that occurs with ifoshamide and the hematologic toxicity. These patients all received mezina, which is also always important in every patient who gets iphosphamide. We need to be thinking about mesna. And there's another concern for neurotoxicity associated with ifoshamide. So this led to a randomized study of BEP times four cycles versus VIP times four cycles published in the JCO in 1998. Thought was maybe this more intensive iphosphamide thing could beat BEP. VIP is vinblastine plus ifosfamide plus cisplatin. The study enrolled over 300 patients with poor risk disseminated germ cell tumor. There is no difference in durable CR rates at two years, which was a little over 60% in both groups. And again, this is only poor risk patients. VIP had significantly more toxicity with more grade 3 or higher hematologic toxicity and GU toxicity despite the use of mesna. There's another randomized study run by the EORTC Cooperative Group, one of the European groups that included intermediate risk patients, again comparing BEP to vip. And that was terminated early after the results of this poor risk trial came out. And again from what they had, there was no difference in outcomes. So really these studies showed that the efficacy outcomes are similar and that that pulmonary toxicity of bleomycin with a BEP isn't worse than the toxicities associated with vip. There is one circumstance though where VIP times four cycles might be favored over BEP times four cycles and that's for primary mediastinal germ cell tumor. This is based on a study published in 2021 from Indiana University. We had discussed that in our one of our earlier episodes that there's a prospective database for testicular cancer patients at the University of Indiana from really the godfather of nearly all of these trials, Dr. Einhorn. They did a study looking at outcomes for patients with primary mediasinal germ Cell tumor. The important thing to remember is that all non seminoma patients with residual tumor after chemotherapy must undergo a resection, given the possibility of a component of teratoma which is chemotherapy resistant. So if you've got this big mediastinal mass, you have to get a big thoracic surgery after. So there's a big question whether bleomycin would impact operative outcomes. There were 255 patients included from the database with primary mediacinal non submonentous germ cell tumor. The postoperative ARDS rates for the whole cohort occurred in 11% of patients and 4% of patients died from ARDs. And again, these are young men who are dying from post operative complications. The incidence of ARDS with BEP chemotherapy was 15% compared to only 2.5% with VIP chemotherapy in the postoperative setting. So this data really shows that we should be recommending VIP times four cycles for primary mediacinal germ cell tumors, given that most patients require resection and the rate of postoperative ARDs is significantly higher with BEP, leading to increased morbidity and mortality.
- [14:49]
A
So that makes sense. So to recap, for patients with intermediate or poor risk disseminated germ cell tumors, we give BEP times 4, which is 12 weeks of therapy after chemotherapy. We resect all residual tumors for non seminoma and that is absolutely mandatory for primary mediastinal germ cell tumors, however, which is also by definition poor risk. We often prefer VIP for four cycles given the risk of postoperative ARDS with BEP times four from that study that Vivek just mentioned. So let's change this case around a little bit and let's say that the same patient had post orchiectomy tumor markers that had downtrended with a nadir that was undetectable. So no detectable AFP and a beta HCG@300 and he now would have favorable risk non seminoma with four small pulmonary mets. So we offer this patient BEP times three cycles or EP times four based on our current treatment paradigm. But where did this data come from?
- [15:51]
C
So as we talked about BEP times four cycles, that 12 weeks of therapy became the standard of care back in 1984. And as we've seen in so many other fields in oncology, there was a push to de escalate therapy in this young patient population. Given the risk of long term neuropathy and ototoxicity with cisplatin and potential treatment related MDS and AML with dotoposide. This led to a randomized study in favorable risk patients of BEP times four cycles versus BEP times three cycles, which decreased therapy from 12 weeks to nine weeks. The study was published in JCO in 1989 and it found no difference in outcomes between the two groups, making BEP times three or nine weeks of treatment the standard of care for our favorable risk patients. We'll have a link to that study in our show. Notes the regimen EP times four cycles has never been directly compared to BEP times three cycles in a randomized trial. This actually comes from a randomized study comparing etoposide plus cisplatin times four cycles to etoposide plus carboplatin times four cycles that was published in JCO in 1993. The study only included favorable risk patients and etoposide plus cisplat had a superior durable cure rate numerically and has similar outcomes to BEP times three cycles. So we kind of extrapolated that this is probably also a reasonable thing to do. There's a retrospective study from Indiana University looking at differences in outcomes for EP times 4 compared with BEP times 3 published in 2018 and we'll link to that study in our show notes as well. Ultimately, there was no statistically significant difference in 10 year survival between these two regimens. The study is difficult to interpret given that it was all retrospective and patient selection likely played a role and influenced the outcomes, but long term survival is over 90% in both groups, again speaking to just the favorable biology of these patients.
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B
So that makes complete sense for favorable risk we have BEP times three cycles, in other words nine weeks of therapy or EP times four cycles, or in other words that in that case 12 weeks of therapy without the bleomycin and both regimens are reasonable given the lack of prospective randomized data comparing these two approaches. This also means that we can drop the bleomycin for pulmonary toxicity and finish out a regimen with EP times four. For example, in this favorable risk group for intermediate or poor risk, remember we have BEP times four or VIP times four. So if there's pulmonary toxicity you would switch to VIP to complete the treatment, not just EP times four for those intermediate and poor risk patients who may have pulmonary toxicity with dabliomycin. I'm going to change the case just a little bit. Let's say that we have a patient with disseminated pure seminoma by histology and this was confirmed as they had no AFP elevation. There was liver METS and bulky retroperitoneal nodal involvement. So he had intermediate risk disease. Given that there was some non pulmonary visceral mets in a seminoma patient, he was treated with BEP times four cycles. At the end of treatment, there are residual retroperitoneal nodes. So Ronak, do we need to resect all residual masses in pure seminoma?
- [18:56]
A
So for these patients, observation is very reasonable if tumors are less than 3cm with serial imaging, as most are just tumor necrosis. And really there's nothing to worry about with regards to teratoma. But for patients with residual disease that's more than 3 centimeters, we often obtain a PET CT scan which has about a 94% negative predicted value and proceed with biopsy or resection if the mass is PET avid. So really it depends on the size of the adenopathy or rather the residual mass to decide what we do next. So it's really critical to know that non seminoma, however, requires resection for residual masses. But seminoma does not find for all the reasons that I just described. It's also remember that if there is a significant tumor growth during chemotherapy, then you should also proceed with resection for what we call growing teratoma syndrome as opposed to continuing chemotherapy. And so we'll discuss more of this when we talk about the surgical management with one of our surgery colleagues in an upcoming episode. So guys, let's wrap up this episode by discussing the relapse and refractory setting. And so let's say we have a patient that got BEP times four for intermediate risk non seminoma and they had pulmonary mets and then this patient develops a 2 centimeter lung metastasis three years later. How would you approach this patient?
- [20:21]
C
The timing of relapse and the amount of relapse disease really matters for these patients. If the relapse is localized and occurs over two years after initial treatment, then surgical resection is the preferred approach. If the relapse is within two years of initial treatment or there's disseminated disease, then we look towards salvage chemotherapy. And so let's say this patient underwent surgical protection and remained in remission five years later. Let's change the case again, let's say we have a patient with disseminated relapse of the disease. What kind of chemotherapy options are we looking for in this salvage setting?
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B
So the data here is very sparse. We only have small single center phase two studies. And there are two pivotal phase two studies looking at two different regiments. One is called TIP and that's taxoliphosphamide, cisplatin for four cycles. And the other one is called veip, which is vinblastine isosamide and cisplatin for four cycles. So for that TIP regimen with the taxol, this led to a roughly 60% durable CR rate in a study of 46 patients. It's really important to know that in that study, the patients that were included were a little bit more favorable. We didn't have as high numbers of these primary mediacental germ cell. There weren't super high numbers of these non, non pulmonary visceral metastatic disease. So take all that with a grain of salt when you're looking at these absolute numbers. The VEIP regimen with vinblastine led to a 25% durable CR rate. So less than that 63% in a study of 132 patients. But notably, again, this is a very different patient population. They were higher risk in this study, so it's hard to compare the two. And the durable cure rate for relapsed primary mediastinal non seminomatous germ cell tumors. So the primary mediastinal tumors was 0% in the relapse setting. So it really shows an area of unmet need. So both VEIP and TIP for four cycles are regimens that are approved in this setting. And we know that TIP numerically had better results, albeit in a more favorably selected patient population. So both are reasonable options in the salvage setting.
- [22:28]
A
These durable CR rates don't look that great in this salvage setting though. So, you know, I'm assuming that as we sort of move down the list of treatment options, things are not looking as great. What are we talking about in terms of options in the third line setting?
- [22:45]
B
So this is the part where we talk about stem cell transplant, which seems absolutely ridiculous. And there were two groups that developed two different regimens for this situation, Indiana University and Memorial Sloan Kettering. So let's talk about Indiana University and what they did. So they did a single center study looking at 184 patients and with either relapsed or refractory germ cell tumors. Because remember, these salvage regimens of TIP and VEIP are reusing cisplatin. So what if you're a refractory? And in a study published in the England Journal of medicine, they had 184 patients. 75% of the patients were actually just in the second line setting. So they hadn't received some of those, the TIP or veip regimens. And 20% were platinum refractory. What they did is they developed a regimen of High dose carboplatin and followed by stem cell rescue. So remember, that's what stem cell transplant is, right? You just save the patient with their own stem cells. And so the thought was, what if we cranked up the dose of the platinum agent, which is what the testicular cancer is really exquisitely sensitive to. And you couldn't do that with cisplatin, right, because your ears would explode and your fingers would fall off from neuropathy. But for carboplatin, it just causes myelosuppression. So they cranked up the dose of the carboplatin, gave it, rescued the patient with the stem cells and said, let's just do it again. So it's a tandem autologous stem cell transplant where they get two stem cell rescues. The durable CR rate was 63%, which sounds like a similar number to the tip data. But this is a much higher risk patient population. These primary mediacental germ cell tumor patients could be cured. And that was pretty big. So that showed a very effective salvage regimen for the Memorial Sloan Kettering. This was also published in 2007 and JCO. And here we have a triplet transplant. So I never thought that a patient would ever get a triplet transplant, but they did it. So they gave all patients taxol and ifosfamide for two cycles and stem cell collection, then did high dose carboplatin plus etoposide followed by stem cell rescue three times. And that might make you think, is this patient going to develop MDS or AML from this high dose of therapy and the selection of the clonal hematopoiesis? When you're really selecting for a pool of that, shout back out to our AML series of related diseases. That's a pretty tough patient population to treat. So you think about that in your head. The durable CR rate in that study was 50%. So not significantly different than the large study, the larger study actually from the Indiana group. So the MSK group, we had less patients, a little over 40 something patients. In the Indiana group, we had 184 patients and the CR rates were higher. All of this has actually led people to think, well, in our salvage setting, we're just reusing a bunch of cisplatin and an alkylating agent, really increasing the risk of leukemia. Anyway, with these durable CR rates, probably in that quarter of patients might be cured in the high risk group. What if we did, in the second line, did a randomized study of the stem cell transplant approach versus the salvage approach with something like a TIP and that's a study called the Tiger trial, which is an international study that's taking the MSK approach to the transplant. So that triplet transplant here at the fellow on call, we kind of wished that it was actually using the Indiana approach with the double transplant due to toxicity in these patients. That trial should actually read out probably by ASCO of this year, maybe a year from now. It's looking at it. It looks like they have enough numbers of accrual. So excited to see the data and see maybe in the second line setting, stem cell transplant will lead to a benefit. But I think it's going to take several years for the overall survival data to mature. And that's what we really care about when we think about these secondary malignancies. And are we just trading one problem for another? So it'll be very interesting to see the data again. Stem cell transplant and testicular cancer is a thing.
- [26:34]
C
Yeah. And it makes sense, right. This is an exquisitely chemosensitive disease. So if you can preserve some marrow in a freezer somewhere and then just give a myeloablative dose of chemotherapy, you have a good shot. And so I'm excited to see this new data too. And remember, like you mentioned, we're talking about autologous stem cell transplant. This is not allo. We're not going and looking for donors. We're putting the marrow in the freezer, blasting the body with chemo and giving the marrow back.
- [27:02]
A
Super cool story, and I'm really excited to see that data come out soon. I feel like, based on our discussions today, it's very evident that not a lot has changed in testicular cancer management in quite some time. So it'll be, you know, almost 20 years since the last bits of data came out in this setting. So that'll be something to look forward to for sure. Guys, I think that wraps up another fantastic episode of the fellow on call. Until next time, we'll see you all later.
- [27:27]
B
See you later.
- [27:28]
C
Peace.