Metastatic Castrate Sensitive Prostate Cancer


DR. RAOUL CONCEPCION: This first case actually is a patient that I was consulted about in July 2020. This is a 63-year-old white male who was having worsening of back pain and progressive left lower extremity weakness requiring increasing doses of opiate. Had some significant medical comorbidities, including history of a cerebral vascular accident in 2012, but well controlled hypertension.

He was actually seen initially because of his low back pain by an orthopedic surgeon. An MRI of his spine showed an expansile lesion and soft tissue quickly went to the L3 vertebral body. So again, this was a spine MRI. It was no evidence of spinal stenosis. There was impingement of this expansile mass into the foramina. And then obviously, as part of it, they also saw a questionable necrotic lower pole mass to the left kidney.

He was referred to urology, where a CT of the abdomen and pelvis was performed, which confirmed this necrotic 7 cm mass to the left lower pole. There was no hilar lymphadenopathy. It was no renal vein involvement and again, the L3 expansile lesion, which was measured about 3 cm, was noted. Technetium bone scan showed increased activity to L3, as well as a questionable area to the left femoral head.

Significant lab, his alk phos was 65. His AST was mildly elevated at 53. His ALT was 114 and his bilirubin is 1.6. So now what I want to do is ask a few questions to the audience and then I'm going to start in with the discussion. So let's go to the polling questions specifically. With regards to percutaneous needle biopsy, I would A number I biopsy the L3 lesion only, 2, biopsy the renal mass, C biopsy both, or D, I wouldn't biopsy either one?

And again, I think will give the audience a chance to opine on this. I think all of us, we know that renal biopsy is becoming more and more important especially when you have this kind of situation where you have a synchronous metastases. The workup otherwise I think was pretty unremarkable. What is the role of renal biopsy, whether it be a metastatic lesion or whether it be of the tumor itself? Historically, urologist have not been very aggressive in terms of pursuing renal biopsy.

And the question is, does this have some value? Let's go to the next question. So given his back and lower extremity pain, I would A, for the patient to radiation oncology for palliative therapy to L3; B, for a patient to radiation oncology for palliative therapy to L3 and femoral head; C, initiate immediate systemic therapy; or D, offer immediate radical nephrectomy, spine stabilization, followed by systemic therapy?

I think obviously again be interesting thing about this particular case is that again, we have a fairly large left renal mass and obviously, though, we've got a lesion to L3 but the fact that he's having worsening pain, especially symptomatic pain in his lower extremity, what is the best way to actually deal with spinal lesion, given pain and given more than likely it does represent a metastatic process?

And then the last question, which is really more sort of an educational question, is the following. The paraneoplastic syndrome often associated with elevated LFTs, estimated SED rate, prolonged PTT and renal cell carcinoma is called Li-Fraumeni syndrome, Stauffer's syndrome, Cowden syndrome, or Lynch syndrome? Again, this is sort of my long history of knowing eponyms and just kind of historical knowledge. So, with that being said, Dr. Kernan, what about the biopsy question?

DR. KEN KERNAN: obviously, in the last couple of years, renal biopsy has kind of become in vogue again. I think we tended to do a lot of it was small renal masses. I think that's becoming more standard of care now. I think for large renal mass like this, I've seen national [phonetic] renal lesions probably not relevant. I think we all know that needs to come out. But I do think biopsy of the L3 lesion to confirm that I think is important. And I think that's probably one of the first steps that we would lean towards.

DR. CONCEPCION: Dr. Garcia, would you agree with that? What are your thoughts? What would you do if this person showed in at your clinic in Cleveland?

DR. JORGE GARCIA: I think I agree with Ken. I think that the person will likely need the biopsy the most before we can treat this patient. Actually, Travis is a radiation oncologist because I don't believe this patient could undergo radiation without a tissue confirmation of his underlying pathology. I think for me the biggest question right now is, is this patient really developing a spinal cord compression or not?

You comment earlier that he had lower extremity weakness so if we believe the scan doesn't show any evidence of cord compression, i.e. spinal stenosis, I do believe a biopsy of the—I think the question then becomes do we need surgery or do you need radiation therapy? And I think what difference here will be if he has a cord compression and has a single level disease, I think that it is fair to say that surgical evaluation will be important.

If you decide to do surgery, that obviously addresses the question of the therapeutic intent of that surgery and also the diagnostic aspect of it. If you were to make that decision that surgery is not the best but rad radiation, the patient will likely need biopsy, prove his histology, move on with palliative radiation therapy to the L3 and then move forward with his management for his kidney cancer.

DR. CONCEPCION: Travis, would you consider radiating this patient's symptomatic L3 lesion without having histopathology? And I guess the second question, knowing that there's various cell types, I'm assuming there is no data. I don't know. Is there any data that one cell type, a clear cell or a papillary, response any better or worse or the same to radiation? But I guess the first question is, would you mandate that before you, and if it was the recommendation to radiate L3 based upon the patient's symptoms, would you mandate having histopathology?

DR. TRAVIS MANDEL: Usually, the mantra is, no tissue don't treat. So, no meat, no treat. Usually, patients will get a biopsy. I think this patient, just to add on I think what Dr. Garcia was saying is completely appropriate and exactly what would typically happen. A couple of things that I would just kind of tag on to this would probably be MRI directed at that area on the pelvis.

They were saying it was a technetium bone scan left femoral head, so yeah, left femoral head, maybe get MRIs, see if there's anything there because of that a met, that might be something that needs to be addressed. Also, if I had a dollar for every brain metastasis from a renal cell that I've treated, I probably wouldn't be doing what I'm doing now. So if it ended up confirming diagnosis of metastatic renal cell, it might be reasonable to get a brain MRI to ensure it is no brain metastasis.

But honestly, like looking at this picture, it's probably renal cell with this giant renal lesion. And I think a surgical consultation would be completely appropriate. But the way that we address these patients with what we call oligometastatic disease is we try to cure them with ablative radiation.It's called SBRT or SABR and these are stereotactic treatments that are directed at the metastatic lesions and then actually sometimes the primaries.

DR. CONCEPCION: Okay, these are the questions and clearly I think, to your point, you've got somebody with all of the metastatic disease with probably a renal cell. So let's say they get the biopsy and it's a clear cell. And again, let's make the assumption that they're biopsy not only L3 but they went ahead and biopsied the kidney mass itself. It's consistent with a clear cell carcinoma. Let's just for the sake of discussion say there is no brain metastases. There's no visceral metastases in the liver or in the long so, in terms of the sequence of therapies here, you've got obviously a number of things at our disposal. You have surgery, which for the most part is palliative nephrectomy. You've got a symptomatic L3 lesion that's getting worse. Obviously I think everybody has made the point. What about the stability of the spine itself relative to whether it's treated or whether you don't treat it right away. Ken, what are you thinking is kind of the sequence of what's the best way to manage this patient, taking into account the fact that he's got oligometastatic disease. He's got a big renal cell, plus he's got a fairly significant L3 lesion that may or may not cause problems whether it's treated but it clearly is causing him pain?

DR. KERNAN: Sure, I think in the old days when everyone was big open surgery, you might think about stabilizing the lesion radiating the lesion first. But yeah, it's a big lesion but it's 7 cm, so that's very consistent with consist of being able to do laparoscopic or robotic nephrectomy. Basically, that's a one day, two day turnaround. It's a relatively simple procedure. They go home in a day or two. And that alleviates a lot of probably his discomfort.

As long as I think the lesion is stable, then you can get him to see Travis in no time and get that radiated. So I think getting the kidney out first doesn't really burn any bridges, gets that done and out of the way. And then we can move forward with his definitive therapy to L3. Again, as long as a stable—now if they say look, this needs to be stabilized first, that's a different story.


DR. GARCIA: As a medical oncologist, I think the data that we have provided is insufficient, Raoul because the data that we have - - his spine is sufficient for me to make by decision as to the sequence of events that I think his spine has to be addressed first. And again, my sequence here would be a biopsy followed by immediate radiation therapy. However, whatever technique one may decide to use - - or not.

Now I think that the bigger question is, this is a gentleman who has, as you pointed out, Stauffer's syndrome so he does have systemic disease because he has paraneoplastic symptoms. But more important than that, we really don't know the prognostic classification for this patient. Clearly, he's going to be an intermediate risk just by virtue of his time from diagnosis to treatment.

But it would be important for us to know whether or not he has anemia, if he has neutrophilia and if he has thrombocytosis, which are three additional key metrics for us to define if you're a a good actor, in the middle, or a poor actor. And I'm talking about the International Therapies Consortium data. It is clear that if you have intermediate or poor risk features, surgery, i.e. standard reduction nephrectomy, even in the context of oligometastatic disease, may not be ideal for this patient population.

On the contrary, if you have a good risk patient, and I think that I'm really referring to the CARMENA data, which is a bit different to how we have practiced in the United States for the last decade, we really never took patients with really aggressive disease, if you will, to surgery. We would really actually cherry pick in those high risk patient population. And I think we stand by that data. So the French data for us really hasn't changed how we practice in the United States.

So if this gentleman is a truly intermediate patient, I would tackle his spine first, see how he responds to that, and then the bigger question is going to be, should I move him to a nephrectomy or should I put him on systemic therapy? And only if he benefits from systemic therapy down the road will we review the role of nephrectomy for him.

DR. CONCEPCION: Travis, give us a little bit of a feel again, assuming that patient has worsening symptoms and it's really his back pain that is causing much of his problem. So if he came to you and give us a feel about the role of just palliative external beam radiation therapy to L3. What does that look like? How many doses, sort of and what is the literature support relative to making patients more comfortable, especially in a setting like this?

DR. MANDEL: I talk to patients about palliation or what I would consider very aggressive palliation with the stereotactic treatments. And so the difference between these two treatments is, for example, this patient came in and he had multiple mets all throughout the vertebral bodies. And he was pointing to some area on his back that was causing him pain. That would be a patient that would get straight up palliative radiation.

And that would be someone you would receive either 8 Gy, 20 Gy in 5 fractions, or 30 Gy in 10 fractions. And that kind of just depends on the radiation oncologist and the setting for this patient. This patient I would probably, since he's 63, sounds like the patient isn't too terrible at health. I would probably try to steer them towards a more aggressive treatment. And when we do these stereotactic treatments, we deliver 20 Gy in one fraction to the lesion.

It's ablative dose and the local control for that is well over 90%. And so the deal is with him is it's causing some kind of like neurologic issue. And what sounds like, it's not a cord issue. It's more of a nerve root issue or compressing on a nerve. And so in those kind of cases, sometimes I think it's really relevant to have a neurosurgeon or orthopedic surgeon look at on that lesion and see if they can get a little bit of compression off that nerve.

Because the radiation, these renal cell tumors they don't, and even in metastasis, they don't shrink rapidly like you would see in a lymphoma or something like that, where you can watch it melt away. These take quite a long time, months to go away. And so I think his actual symptom that we'd be palliating, we could probably make it worse actually because the lesion may swell or for something like that.

But if this lesion wasn't involving the nerve and it was just in the vertebral body, I would hit it hard with 20 Gy and then I usually send those patients off to be evaluated for a vertebroplasty or something like that to stabilize the spine.

DR. CONCEPCION: Jorge, I'm going to let you finish up here because you alluded to it. So let's just, for grins, let's just say he gets radiation, has a decent response pain is better, feel functional. So now we're looking at again palliative nephrectomy but also systemic therapy. Briefly, what does the data suggest? Is there value and what agents of adjuvant or neoadjuvant versus adjuvant therapy—

DR. GARCIA: Yeah, that's a great question, Raoul. So these patient obviously, assuming that he has intermediate or poor risk disease by virtue of his presentation, the standard of care, systemically speaking, for him would be to receive either ipilimumab and nivolumab, which is the CPI, the checkpoint inhibitor combination, or to receive axitinib plus pembrolizumab, which is the other regimen of choice in the frontline space in the - - risk stratification.

I think that you'll find two pockets of practice in North America that are not driven by data but rather my expertise and experience and to some extent by bias as to how you were wounded and trained throughout immunotherapy era of the 90. So you'll find a pocket providers who will believe that ipi nivo, ipilimumab and nivolumab will be the standard of care for him. And you'll find another group of providers that will say you know what?

Because he may be a rapid response, let's just give him a TKI based approach along with immunotherapy so we can actually have a better what I would call a more rapid response to treatment and maybe even gain a PFS. That would be the standard of care right now systemically and I think that in my practice, outpatient like this I probably will start ipilimumab and nivolumab. That's my own personal bias.

I think that both regimens, as you know, have survival benefit, have the ability to lead to stable disease, RECIST defined partial responses and also complete radiographic responses. More important than that, over the last two weeks, the Check 9ER data was presented at the European meeting at ESMO. And that data clearly also looking at the combination of another TKI called cabozantinib, which is a dual KDR and c-MET inhibitor in combination with nivolumab, also a significant improvement in PFS and secondary endpoints of survival.

And lastly, last week there was a press release by what we call the CLEAR data, which is a phase 3 trial in the frontline space looking at the combination of everolimus and lenvatinib, which is a KDR and an FGFR inhibitor, again, sunitinib as historical control, again is the combination of lenvatinib and pembrolizumab. So the jury is still out there. We have to wait and see what that data looks. But it is possible that over the next 12 months, we may have for regimens in the frontline space that are competing for the same patient population.

DR. GARCIA: — question of surgery, we don't have great prospective data looking as to once you get therapy, what is the role of debulking nephrectomy, if you allow me to use that expression, acting to achieve stable disease or PR, CR, outside your renal mass? That data is still out there, although anecdotally.. Some of us do it. I don't think we have sufficient prospective data to support that approach.

DR. CONCEPCION: I think the thing about it is, and I think we have to move to the next phase, is the fact that contrary to, excuse me, in contrast to 20 years ago, obviously we have better systemic therapies. We always have. We're better surgically as can, you pointed out, robotically and obviously our radiation technique continues to get better and better. Okay, so let's go on to the next case here.

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