High-Risk Renal Cell Carcinoma: 51-Year-Old Male


Around the Practice: High-Risk Renal Cell Carcinoma

Dr. Raoul Concepcion: Let's go ahead and get into case 1, which is a high-risk renal cell cancer case. So this particular patient is a 51-year-old male who presents with left flank pain and gross hematuria. Past medical history is significant for type 2 diabetes, hypertension, elevated cholesterol, hypogonadism, depression. Surgically he's had a right inguinal hernia. He has allergies to aspirin, iodine contrast, walnuts and cats. He's on a number of medications, including glyburide, statins, lisinopril, which are all listed.

His review of systems is noncontributory. He is married, significant occupational exposure, does have a significant family history of esophageal cancer in his father. On exam, he has no abdominal masses and doesn't really exhibit any cutaneous lesions. Evaluation, he has a CBC, BMP, LFT's, all normal, slightly elevated alkaline phosphatase. On CAT scan imaging, we do not have a representative of this, but he has a large enhancing left renal mass about 11 centimeters, no lymphadenopathy, no evidence of metastatic disease. Chest X-ray no evidence of mets, and none is also seen on bone scan.

After shared decision-making the patient opted for a left robotically assisted radical nephrectomy. Final pathology showed mixed clear and granular cell type, tumor itself was 10 by 7 centimeters. Fuhrman grade 3 had invasion into the renal vein, but negative margin at the renal vein resection site. But he also has extension of the tumor into the peri-renal fat, renal sinus adipose tissue, but Gerota's fascia was not involved and it is intact, so he has a pathologic T3N0M0 lesion.

So poll question number one, I would offer this patient adjuvant therapy? A, yes. B, no. C, unsure. So would you offer this patient adjuvant therapy for his T3 disease?

Let's, let's talk about this a little bit.

So we've got a patient with a mixed granular and clear cell histopathology type. We have invasion into the peri-renal fat, but Gerota's fascia is intact, he's a pathologic T3 lesion. So, Dr. Tripathi, tell us a little bit about how you would manage this patient, especially in light of some of the existing therapies that are now approved for this, for what I think is now this high risk patient?

Dr. Abhishek Tripathi: Absolutely. So high-risk renal cell carcinoma has been an area of active research for the past decade, if not longer, it's about 15 trials trying to investigate different adjuvant therapies in that same space. And that resulted in the approval of one of the agents sunitinib in the adjuvant setting for high-risk renal cell carcinoma, which I think this patient meets the criteria for. However, this happens to be one of those situations where even though there is an FDA approval, there's not widespread consensus, whether we should be offering or recommending strongly these therapies for patients with high-risk disease.

And the reasons for that is because of the discordance between the results of the Ashore and the Resnick trial, and even within the trial itself, the lack of an overall survival benefit to date, taking that into account a high rate of grade three adverse events that we see with sunitinib (Sutent)s, anybody who has just prescribed it knows that these can be somewhat challenging to administer to the patients and get through the 9 months or 1 year of treatment.

For that reason, our practice is to try to enroll patients in the clinical trial and if a clinical trial is not available, then we have a balanced discussion with the patient regarding the available literature. And majority of the times in our experience the patients have ended up declining the adjuvant sunitinib after understanding what the data shows and what the data lacks currently. Interestingly, even though the sunitinib is actually approved in the US, it was a quite hotly debated topic at the time of approval itself in the ODAC meetings with FDA. And NCCN actually has a category 2B recommendation on using sunitinib.

So this is one of those rare circumstances, that'd be have a positive trial, but didn't necessarily did not change practice. And when we took the same question to the European Medical Agency, they recommended against the use of sunitinib considering all elements of the data together. And taking those things into account, I usually discuss the data, the adverse event profile, and I don't strongly recommend it, but it is an option for patients if they choose to do so in the adjuvant setting.

Dr. Raoul Concepcion: Interesting, so we have an agent that's FDA approved, has gone through the trials, but yet NCCN gives them a 2B recommendation, that's interesting. Vahan, when you run into these patients, surgically, is that sort of what's happening in, in the Atlanta region also? Are you talking to them about the role of adjuvant therapy in this high-risk patient? Are you recommending them see medical oncology? What has been your practice pattern?

Dr. Vahan Kassabian: Yeah, I mean, I totally agree. I have found that every single patient that I sent to medical oncology colleagues for discussion and therapy with sunitinib, all declined for the reasons already explained. It was a category 2B recommendation, had a lot of toxicity grade 3, and it was for at least 9 months and there was a lot of dose interruptions and dose reductions. So basically, the consensus was that every patient I referred declined to have therapy.

Now, just a couple of points for this particular patient, although he had a robotic surgery, I don't do robotics, I think this patient would have been a great candidate for open surgery, given the size of the mass, that's a different point. The other point I want to make is that, at least in the metastatic setting of renal cell carcinoma, uni-modality therapy is being replaced by multi-modality therapy, especially immunotherapy.

So I see in, in, in the future that perhaps single agent therapy would not be efficacious in the high-risk patient following nephrectomy such as this, but I think multi-modality therapy may be more efficacious and probably widely accepted.

Dr. Raoul Concepcion: Paul, is there any role for radiation in a high-risk patient in the adjuvant setting?

Dr. Paul Kim: Yeah, there's not many good quality data in terms of randomized trial. I think one of the few that were ever published were a couple of decades ago. I think there was a Copenhagen study, not many = patients and they just didn't find much of a benefit in terms of overall survival. They gave about 50 gray for what they perceived to be high-risk pathologic features that would increase the risk of local recurrence. But, you know, I think part of the challenges is that, you know, once you remove the kidney, it gets filled up with bowel. And bowel is [inaudible 00:11:44] some of the most sensitive organs to a radiation to try to deliver a therapeutic dose is difficult. And, that is contributed to some of what we're seeing the data that there's not much of a clinical benefit.

Dr. Raoul Concepcion: Okay. So poll question number two, based on the pathology... so again, this was a mixed clear cell, and is there a role for genetic testing? A, yes. B, no. C, unsure. So I think all of us, as we progress on in most GU cancers, especially for prostate obviously, but we are becoming more and more focused on the role of molecular testing, the role of hereditary testing. And we do know that there are certain histopathologic features where it might lead one towards looking for a hereditary profile.

You know, it's usually not the clear cells where people really get suspicious, but there are a number of renal cells that are out there, especially these ductules and these collecting duct tumors that are now being completely reclassified, but obviously clear cell is not one of them.

So this is the same patient, 6 months, CT of the abdomen, pelvis chose some... in the lower lung fields, some sub centimeter nodules, a dedicated chest CT shows nodules in the right 4 nodules in the left, largest being about 7 millimeters, continues to be on follow-up at 12, 24, 36 months with no change, but 4 months post-resection has another chest CT. So now he's 4 months post-resection, has a bilateral noncalcified pulmonary nodule, which has increased in size from 10 millimeters to 16 millimeters.

Pet CT was done, which showed significant uptake in pulmonary nodules noted bilaterally, no significant uptake in pulmonary nodules bilaterally. However, there is a mild uptake noted at the left lung base, which is basically 2.6 on delayed. So with that in mind, I would offer this patient A, number one needle biopsy of the pulmonary nodule. Two, refer to thoracic surgery for potential extra pain of surgery. C, continued observation. D, other. So let's go ahead and start the voting.

Vahan, while they're voting, so this is the patient now, who you've kind of described as maybe developing now metastatic disease 4 or 5 years out. What do you think about increase in this nodule from 10 to 16 millimeters?

Dr. Vahan Kassabian: Yeah, I think it's significant. We're always concerned that these are metastatic sites, even though they're small, but they're clearly growing. And, you know, given his pathology and he had this huge mass at such a young age, he has a high chance of recurrence and obviously now he has something that's visible. And I would think that, starting off with a biopsy or a section, whichever one I think is perfectly reasonable to prove or disprove that he has metastatic disease before initiating therapy.

Dr. Raoul Concepcion: Yeah. And I think our audience agrees with you that they would definitely share the same concerns. And, lo and behold, this patient actually was referred to interventional radiology, had a CT guided core biopsy of the left upper lobe nodule, which was negative. And then also had a left thoracoscopic ledger section left lower lobe wedge section in bronchoscopy, pathology on both lesions shows, metastatic renal cell. And again, just like this primary, no surprise mixed clear cell and granular type, pleura and margins are negative. So now, we have a patient with documented pulmonary metastatic disease that has been resected. Dr. Tripathi thoughts at this point.

Dr. Abhishek Tripathi: Yeah. So this represents, so to speak, a little bit of an internal discourse between how the patient initially presented and now how is he behaving? So initially he had quite aggressive disease, locally advanced a minor D3 disease. But if after the resection, he had relatively [inaudible 00:17:11] for about 4 years after which he started developing growth in the pulmonary nodule. So based on the INBC criteria, I think he belongs in the favorable risk category and he was treated appropriately, so with metastasis-directed therapy … we can think about it in a couple of ways. This is potentially a patient that has favorable risk disease, has shown indolent biology over the past 4 years with recent change in dynamics, obviously, but it's still potentially any deep. So I think one option would be to follow the patient closely. And we have had longitudinal data on the subset of patients who have low volume disease, and have shown indolent biology and undergo metastasectomy and they can be followed post-surgery for a considerable amount of time.

And there are potentially 2 areas that have data that can help us inform that, one would be the post-metastasectomy biz-op ANAB data that was presented in 2019 that showed us that post-metastasectomy biz-op ANAB in patients who were rendered potentially NED, didn't really impact the overall survival and the survivals are actually worse in those patients.

And secondly, we have a lot of retrospective and corroborative data published recently that a significant subset of these patients can actually follow along and delay the need for systemic therapy for a year and a half of the median, and potentially longer. As our therapies are getting more and more effective, the patients are being, uh, on these therapies for much longer times and the cumulative toxicity, both financial and physical could actually bear on these patients.

So we have to be careful about the decision about starting systemic therapy in these patients. That being said, I think if there was a patient in whom there was still residue nodules and measurable disease left in that case, I would start that patient off in the combination regimen of a measure of [inaudible 00:19:24] emitter and immunotherapy, as we have learned over the past couple of years, that have shown improved overall survival compared to single agent TKI therapy over the past several years.

And I think the, the regimen of choice is probably dependent upon the comfort of the treating physician with terms of management of adverse events. They all have an overall survival benefit over sunitinib, which was benchmarked previously. So this includes axitinib (Inlyta) and pembrolizumab (Keytruda), then Lenvatinib (Lenvima) and pembrolizumab, cabozantinib (Cabometyx) and [inaudible 00:19:56]. All 3 regimens are reasonable to consider in that situation. Innovation is interested in pursuing systemic therapy.

Dr. Raoul Concepcion: So, basically you're saying that if the patient had measurable disease, that more than likely you would proceed with a doublet of an OTKI and an immunotherapy, but in this particular case, given the fact that we don't really have any other evidence of metastatic disease, that's measurable than basically watching this patient is observation is also an option as well, correct?

Dr. Abhishek Tripathi: Yes, yes, absolutely. And rational for that is to avoid any side effects for the longest time that we can avoid to delay those measurements.

Dr. Raoul Concepcion: So we talked about OTKI and its side effects. Is there a role for monotherapy immunotherapy in this particular patient, is that approved or what's the data on that?

Dr. Abhishek Tripathi: Yeah, so we have data on that, Nikita 427 trial investigated pembrolizumab monotherapy in patients with favorable-, intermediate-, and poor-risk disease, and had a response rate of about 27% or so. There was no competitor arm with that, so although the patients had a durable response and some of these lasted a long time, there was a competitor arm, and I think that's not how the agent is actually approved of this point, but it is a very rational question during to understand who needs intensification in both patients and who needs these, who could get by with just monotherapy.

I think biomarkers would play a role potentially. There is some data that suggests that favorable risk patients that are driven by vascular endothelial growth factor group in tumors. And these tumors are sensitive to, and more likely to respond being,[inaudible 00:21:59] we do a tyrosine kinase inhibitors, but obviously we have a subset of patients responding immunotherapy, but just better tolerated. So the monotherapy with PD-1, I would not consider it standard of care, and I would consider it only as part of a clinical trial in this situation, considering the available randomized data and the FDA label.

Dr. Raoul Concepcion: Let's throw a little bit of a kink into this one for a second. So let's just say the patient had this presentation, had this resected and then maybe also has a concomitant positive bone scan. Let's just say that as we know bone is not all that common in renal cell, but it does obviously occur. Dr. Kim, the role of radiotherapy, we obviously used quite extensively for prostate, what about bone metastases in the setting of renal cell? How do those patients generally spawned with bony metastases and radio and radiotherapy?

Dr. Paul Kim: So, renal cell is a histology that is considered 1 of the more radio resistant types. And so, you would need a pretty high biological effective dose to deliver a plate of therapy. Unfortunately, the technology has matured where we are able to do that, and now it's supported by data like the comment data that shows patients with limited all metastases that you can improve clinical outcomes by delivering ablative therapy and a case like this up to 5 metastasis, so that is being done more and more these days ever since this data published.

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