Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer
Also referred to by the KCA as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC
UT MD Anderson Cancer Center
KCA National Patient Conference: April 14, 2012
The topic “Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer” is near to my heart and in active research at MD A
nderson Cancer Center. The vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable.
Again, as to stage, the vast majority of patients present to us with locally advanced disease, and the reality is that almost half of patients with kidney cancer will at some time develop metastatic disease, which we all know is currently not curable. (Editor’s note: my stage IV RCC with innumerable lung mets in 2004 is now in remission or “cured”, or close enough to “cured”, that I must add this note. It is still shocking to understand that Stage IV RCC is considered incurable. PZ)
Six years ago, we did not have much to talk about. I could show this slide and sit down. For locally advanced disease, we took out the kidney; for stage IV disease, we took out the kidney and gave systemic treatment, usually cytokines.
Now we almost have too many therapies and don’t know how to use them all. How do we integrate surgery into the context of these treatments that we offer patients with metastatic disease? The sad reailties of this are no home runs. These therapies control the disease for some time in these molecular pathways they target. But in most patients, resistance will develop and they have to move on to the next treatment.
I will talk about how we integrate surgery into systemic treatment in 2012, the role of cytoreductive surgery, and then introduce the idea of pre-surgical therapy, something that we have been studying here at MD Anderson that has shown some promise.
These are two randomized trials, one in the US, the other in Europe, which demonstrate the benefit of patients undergoing cytoreductive surgery. The first is the EORTC trial where patients were randomized to upfront surgery followed by interferon, or by interferon alone.
Next is the SWOG (South West Oncology Group) trial done in the US, again demonstrating the value of undergoing a nephrectomy prior to interferon, versus interferon alone? Frankly, many surgeons referred to this trial as “Surgery followed by ineffective therapy is better than ineffective therapy alone.” You can see by these that the response was only 3-4%.
Now that we have more effective therapy, what is the role of surgery in the context of patients with metastatic disease? We don’t even know why cytoreductive surgery works. Does it just reduce tumor burden? Does it produce some sort of immunologic phenomenon where tumor antigens are exposed or is there an immunological “sink”. Is it an alteration in the metabolic milieu where taking out someone’s kidney and altering the ph in the body somehow is anti-tumoral? Or is taking out the “mother ship”, where some sort of endocrine or paracrine phenomenon that promotes metastases. We have absolutely no idea how it works.
Why not take out everybody’s kidney in the setting of metastatic disease?
The morbidity and side effects can be significant, and people can die from this operation. Though it has been proven beneficial in the context of interferon, and it’s quite possible that patients will spend the majority of their time left on earth recovering from surgery. We’ve seen metastatic disease explode post-operatively. Those patients never even get to go on to targeted therapy after surgery. Perhaps these new therapies will cause the primary tumor to shrink. Maybe we don’t need to take out everyone’s kidneys in the face of metastatic disease.
The French are testing this in their Carmena trial. Patients are randomized to an upfront nephrectomy followed by Sunitinib versus Sunitinib alone. It is a non inferiority study design, and the randomization is 576 patients. There is a problem; the trial is not at all accruing very well. Patients don’t like to have surgery randomized, with a computer saying, “You’re going to have surgery, and you are not”.
With the slow accrual to this trial it will be many years before we have an answer. Sunitinib may not even be relevant at that time. And what are we doing for patients in the meantime? Should I take the kidney out or not?
There is evidence that removing the kidney in the presence of metastatic disease is beneficial, from retrospective data derived from the expanded access trial with Sunitinib. These patients had their
kidney removed, not just cytoreductive surgery, but any time in their past.
They were compared to patients treated with their kidney in place. Patients who had their tumor out had a much better response rate than those treated with their tumors in place.
They also had a better progression free survival (PFS) and a better overall survival (OS) than patients treated with their primary tumors in place. Now this is retrospective, it is biased as it is not clear why the kidney was left in place for any one patient. That might have been because the patient was on death’s door and could not have had the kidney removed. But the data shows a benefit of being treated without having your kidney in place.
Newer data from Dr Toni Chouieri at Dana Farber compares are patients who presented with their primary tumors in place. Those who had the kidney removed prior to targeted therapy had a (overall) survival more than doubled compared to those treated with the primary tumor in place.
Those retrospective and (with patient selection) bias, it gives some guidance there may be some benefit to the removal of the kidney in the setting of targeted therapy.
Lecture continues as PART 2 with topic:
Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone
(The lecture is from a patient conference, and may be seen by clicking through to YouTube. My transcription may make it easier to STUDY the information from Dr. McDermott and to review the slides.)
Dr. David McDermott; Dana Farber Harvard Cancer Center; KCA Conference
April 14, 2012; MD Anderson Cancer Center; Houston, TX
“This is a great opportunity to talk about this new research. The last six years brought great advances to the treatment of metastatic kidney cancer with newly approved therapies. No other area of cancer that has had made more progress with new treatments in that time, and there is more good news to come.
In this era of targeted therapies, some have asked if immunotherapy–once the only option for kidney cancer–has any role. In the next twenty minutes, I will show you that it probably still does–for the proper patient.
Dr. Wood talked about limitations with the targeted therapies, the anti-angiogenesis drugs. They are excellent at pruning the tumor, much like I do with my weed whacker. Though they can delay progression, and improve survival, you need to be on treatment to have its effect and all these tumors come back. Once you are off treatment, the effect wears off. They can delay progression, extend life and patients are living longer.
There has been a greater understanding about how the immune system works over the last 20 years when this was introduced.
The Immune System
Adaptive defense system that protects an individual from invading microorganisms
The immune system is specific
Involves multiple large polypeptides that function in:
Antigen presentation
Antigen recognition
Intercellular signaling
Involves multiple cell types Slide 2
These insights can improve outcome for our patients. The immune system is a defense system, which protects the person from invading bacteria and viruses. This system contains multiple moving parts and multiple cell types.
Here is a cartoon example of all the different cells and antibodies, which can protect against bacteria, others that can target a microorganism, or more importantly, a tumor cell. This system was not designed to fight cancer; it was designed to fight infection. That means it is designed to turn on when you have an infection like a virus, and when the virus is controlled, the same “turned on” cells of the immune system are then shut off. These shutoff mechanisms are in part responsible why cancer can evade the immune system, and why it has been so difficult to use the immune system to fight the cancer, as opposed to fight infections.
Different approaches are being used with the immune system to fight cancer, some we’ve used in the past and some exciting new approaches currently being tested. The first approach is much like pressing on the gas. This approach to immune therapy has mostly involved cytokines, with interleukin 2 and interferon, and was used for a long time. They rev up the immune system and are growth factors that stimulate a lot of the parts of the immune system, such as T-cells.
Dr. Wood said there were no home runs for patients for Stage IV kidney cancer, but that is not exactly true. There are very few home runs, a few patients with stage IV disease who obtain a remission of their disease. Remission means treatment of Stage IV disease in which the cancer goes away, treatment stops, and cancer does not come back. To most patients, that is their goal. Very few patients meet that goal, but for some that remission has lasted decades.
Pressing on the Gas of the Immune System
It is also true that this “pressing on the gas of the immune system” does not work for most patients. It is hard to identify which patients it will work for and is associated with lots of side effects. To be effective, as with interleukin 2, these treatments must be given in a hospital. They involve serious side effects, sometime life-threatening side effects, so the kind of patient who can receive this type of treatment is relatively limited.
At Beth Israel Deaconess in Boston we try to be selective choosing patients for this therapy. We try to identify the patients who may receive the home run, before we put them through the side effects, because so many patients go through the side effects without benefit.
High-Dose Aldesleukin “Select” Trial in Patients with Metastatic RCC
D. McDermott, M Ghebremichael, S Signoretti, K Margolin, J Clark, JSosman, J Dutcher,M French, and M Aktins on behalf of the Cytokine Working Group
We had clues about things that might improve the selection, so created the IL2 SELECT trial, reported at ASCO two years ago. The activity of IL2 in this era of these new treatments is still relatively good, as good as it was 20 years ago. The response rate in this trial with 120 patients was 25%, significantly greater than it was when the drug was introduced 20 years ago. The drug is not any better, or are we any better at giving it. But we are better choosing our patients. Choosing who should get it, and who shouldn’t, and that improves the responses of our patients.
It has been known that patients with non-clear cell are less likely to respond to immunotherapy, so in this trial there were very few patients with non-clear cell cancer—and no responders in that group. It is also known that patients who had their primary tumor removed when they presented at Stage IV disease are more likely to respond to immune therapy. In this trial, 99% of patients had that surgery before they went into this trial. It is almost certainly true, that with new therapies available, that the types of patients being referred to an IL2 centers like ours is probably different. Changing the types of folks we are treat means our numbers are improving somewhat.
To improve the selection process and based on earlier research, we wanted to show that certain features of the patient’s pathology of the tumor might predict for response. We looked at what the tumor under the microscope and special proteins (CA IX or carbonic anhydrase IX) that the tumor might produce. We thought those things might predict either high chance for response or low chance for responding to treatment.
Unfortunately for me as a researcher, although fortunately for the patients who went on this trial, the folks who were in the poor risk group–those we thought would not benefit from IL2–did just as well as those not in the poor risk group. It surprised us and showed the importance of testing theories in the proper trials. We clearly need to do more work in this direction to find something to explain why some people benefit and some do not. And it may turn out that response may have more to do with the patient’s immune system than the cancer as how they benefit from treatments that boost the immune response to cancer.
RCC IL-2 SELECT Trial; Conclusions
Tumor features did not predict for response.
Efforts to confirm other predictors are ongoing.
Lessons from this work may guide the development of targeted immunotherapies in mRCC(e.g. CTLA-4, PD-1 antibodies) Slide 9a
So in conclusion for this trial, the tumor features did not predict for response, but we had a higher response than we expected higher than 20 years ago. This work continues and some of this work will educate us as we go into this new world of targeted immune therapy for kidney cancer.
So as discussed, the immune system is not designed to fight cancer, but to fight infections. This graphic shows where the immune system turns on in response, and at its greatest, starts to shut off, as it is designed to do. The shut-off valves of the immune system–the brakes–are in some ways stronger than the gas pedal.
Releasing the Brakes
In the laboratory over the past ten years we have been able to identify what are those brakes are. Now we ask how to block those brakes. One of the most important brakes on the immune system is a protein called CTLA-4 (CytotoxicT-Lykmphoctye Antigen 4). We can block the action of this protein, to release one of the most important brakes to immune response to cancer.
On this slide you see the T-cell on the left, an activated T cell, as it activates a protein, turns itself on. The same T–cell that turns itself on, puts out a protein on its surface, called CTLA-4. When that CTLA-4 protein comes in contact with another protein on that cell, an antigen-presenting cell, it actually shuts off the cell, a natural way of shutting off the immune response. That way these cells don’t overreact to an infection and attack healthy tissues, Now we can interrupt that interaction by bringing in a monoclonal antibody, which interrupts the connection between CTLA-4 and important proteins of the immune system. So we can block the natural shutoff that many patients experience.
Does that work to clinical effect with kidney cancer patients? The short answer is it does. Data presented in the New England Journal of Medicine two years ago. Blocking this protein in melanoma gave improved outcomes, and this was an out-patient treatment, intravenous, given every three weeks for four doses. It’s actually been shown to improve survival for patients with metastatic melanoma.
Blocking CTLA-4
And it’s not treating the cancer; it’s treating the patient’s immune system. The immune system is going out and detecting the cancer in ways that it might not have before getting this antibody. It is outpatient therapy, but it is still associated with significant side effects. Most of those are auto-immune side effects, where the body is now being attacked by its own immune system. Some of these are been quite serious and patients have died from this treatment. We are getting smarter at managing the side effects so there are fewer major complications, but do not get the impression that it’s not serious treatment. It’s less toxic than IL2, can be given to more patients, but still has side effects.
Ipilimumab in mRCC
Single institution (NCI), Phase II trial
Major response rate of 9%.
Max dose test 3/mg/kg. (Dose response in melanoma)
Survival effect in melanoma despite low response rate.
Additional studies alone and in combination warranted. Slide 14
This data led to FDA approval last year of Ipilumimab, now called Yervoy. It was approved in melanoma, but it has been tried in kidney cancer patients at the National Cancer Institute in a very small 36 patients, phase II trial. The response rate, the chance that the tumor shrank by half, was only 9% in this trial. That may not sound great, it was tested at a dose which may not be the right dose; higher doses of treatment may be tested in the future. In melanoma we saw improvements in survival and saw lasting remissions for Stage IV patients. We saw those benefits even with a very small response rate. Go to the “Blocking CTLA-4” slide, and look way out on the survival curve towards the end. These are patients out 3 and 4 years, still in remission and off treatment. That happened even though the response rate to treatment wasn’t very high. It is possible that we might see a long-term benefit for some patients with kidney cancer with an agent like this. Some others are being tested in the coming year, so I would be thinking that additional studies with this approach are certainly warranted.
Steering the Body’s Immune System
We need not just the “accelerator” and the “brakes” to make these things work. We also need improved steering. Investigators want to improve steering by giving patients vaccine approaches. This may get patients’ immune systems to recognize proteins found on the tumor, to wake up and to go and attack those proteins, and to try to control the cancer. These approaches are now in phase III trials that have shown some encouraging results, where we will get some answers.
The agent AGS-003 is being combined with the most commonly used drug for kidney cancer, Sutent. Patients are randomized to use either Sutent alone or Sutent with this drug. Whether this will lead to more response rates and to more long term benefit than with Sutent alone remains to be seen. At least we will get an answer from a large Phase III trial. One of the problems with immunotherapy trials over the years is that they haven’t been large enough to give us clear answers. But this trial is enrolling patients and there are others like it.
Putting up the Barbed Wire Defense
Since we’re in Texas, so I thought I’d give you a barbed wire analogy. One way in which tumor cells evade detection by the immune system putting up this “barbed wire” on their surfaces. When a T-cell comes, tries to sniff out the cancer cell, it is shut down, as opposed to going on to kill the tumor cell. We now know a little bit about that natural barbed wire which comes into play with this particularly important protein interaction, the programmed death pathway, and what that stands for is the inactivation, or the programmed death of the T-cell, which acts like barbed wire.
Why is this important? In kidney cancer, many patients’ tumors are coated with this barbed wire. Patients who have this on their initial tumor specimen have been shown to be more likely to have more disease recurrence in the future. Since we can identify the barbed wire, can we block its activity and lead to an improved effect? The question is, can we target this protein and can we improve outcomes? There is early evidence that maybe we can. This is a Phase I trial, admittedly very early.
Programmed Death (PD)-1/PD-L1 Pathway: The Basics
Several tumor types, including RCC, have been shown to over express inducible PD-L1
Over expression of PD-L1 by RCC tumors has been shown to be associated with adverse clinical/pathologic features, including the following:
More aggressive disease
Shorter survival
Also report to impair tumor immunity
Can PD-1 pathway blockage head to clinical benefit? Slide 18
Phase I Study to Evaluate the Safety and Antitumor Activity of Biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in Patients with
Renal Cell Carcinoma and Other Advanced Refractory Malignancies.
Patients received an outpatient treatment, intravenously, with a drug that doesn’t even have a name yet, BMS-936558, a PD-1 anti-body. This is blocking the interaction between the barbed wire and T-cells. In this trial it is given every two weeks; on other trials it’s been given every three weeks. Patients were allowed to stay on this drug for up to two years as long as they were getting some clinical benefit.
SAFETY RESULTS; ALL PATIENTS
For the entire group, MTD (Maximum toxic dose) was not reached at doses of 1, 3, and 10 mg/kg
There was no apparent relationship between drug dose & AE (adverse effects) frequency
One treatment-related death
Grade 4 drug-related pneumonitis Slide 20
The main reason to do a phase I trial is to test the safety of the drug. This drug was found to be relatively safe, and we got up to the highest dose without getting into serious side effects. There didn’t seem to be a relationship between the dose and the side effects, which was good. There were still 10-15% patients who had serious side effects. In this group of kidney cancer patients and there was one treatment-related death, due to an inflammation in the lung that was probably contributed to by the drug.
SAFETY RESULTS; ALL PATIENTS
Any grade, drug-related (investigator attributed*) serious AEs (SAEs) occurring at a frequency >1% in the entire study group (n=126)
Total with an SAE=11%
Investigations=3.2%
Endocrine disorders=2.4%
General disorders and administration site conditions=1.6%
Hepatobiliary disorder=1.6%
Neoplasms benign, malignant and unspecified=1.6%
Respiratory, thoracic and mediastinal disorders=1.6% Slide 20a
This trial of 126 patients was a much larger group and not just a kidney cancer trial with five cancer types in this trial. There are now 300 patients in this trial, and we’ll get more data in the next several months. But in general the safety population is much larger than the efficacy population. The main point here is that serious adverse events occur in about 11% of all patients, much less than in HD IL2 and CTLA-4.
What did we see in terms of effectiveness? For the first 16 patients analyzed, we saw five partial responses (31.3%), and three patients (18.8%) with stability that lasted over six months. About 50 % of patients were getting some clinical benefit with this antibody. Once again, a small number of patients tested.
Here is an example of the patients we studied, a young man who was diagnosed in 2009, received IL2 and progressed, received Sutent and progressed, had disease in multiple places, including the kidney and the bones and lungs. You can see the before and after pictures after receiving two courses of treatment of ipilumimab with a significant response in the lungs, which is ongoing therapy after two years.
We’ve also seen responses in some unusual places. One place that a lot of our VEGF targeted patients fail is in the bone. This is a patient, before and after, who had a response with a bone metastases you can see here (left scan), and actual healing bone (right scan), just a year later with treatment. That’s certainly an encouraging result for us.
How long do these responses last?
For this admittedly small group, it looks like the major responses for a majority of these patients who had a response, that response lasted over a year. Most who had a response still have that response at a year. Whether that response will continue or stop, when the drug is stopped, remains to be seen. That will be a very important question. But the good news is the patients can tolerate this treatment for a year or more.
In summary, the PD-1 antibody concept is very early, but it has displayed reasonable side effects at all doses we’ve tested, and we seen some anti-tumor activity in some patients with kidney cancer.
PD-1 Antibody Summary
At this EARLY point, BMS 936558 has displayed manageable side effect at all dose levels tested
Anti-tumor activity observed in a small number of patients with RCC
Responses may be durable?
16 patients added to this cohort-ASCO 2012
Responses in NSCLC
Trials launched in 2011 in RCC:
Dose finding Phase II study in patients with prior therapy
Biomarker Trial
Combination RX + VEGF TKI (Phase I)
Were these remissions, i.e., durable, or just responses? Will the patients’ tumors grow after we stop the drug? We don’t know that yet, but we’ve added 16 more patients to the study. We will present data at ASCO in two months (6/12), with more information on this anti-body soon. It is important to note that with this drug and for the patients on it and for the field of immunotherapy for cancer that we are we seeing responses for kidney cancer and melanoma, where we’ve seen immune responses before. It is quite important also that we are also seeing responses in lung cancer. Should that be true, that will bring a lot of energy into the field going forward, as lung cancer is obviously a much more common illness, with very few options available.
There were a lot of new trials launched in 2011. We’ll have a Phase II trial in 2012, including multiple doses, to find the best dose in this treatment and also in combinations with other drugs like Sunitinib to find the best combinations.
So for those who say, “Is there a role for immunotherapy for RCC?” I would say there’s been a lot of progress over the last 30 years in the field of immunology, and we can now better target immunotherapy, and it’s worth preserving.
Is there a role for immunotherapy for mRCC?There has been progress in the field of immunology in the last 30 years
Immunotherapy can be “targeted”
Immunotherapy is worth preserving Slide 25
There is a role for immunotherapies shown by survival curves like this; this is from the SELECT trial mentioned before. These are patients who responded to treatment, now out three years, off treatment. The 13% percent of these patients, 16 patients have that benefit which really achieves the patient’s goal, which is worthwhile to try to get for more patients. It is proof of principal that we can do this, but we need to do it for lots more patients. If we work on this, hopefully we can achieve Dr. Wood’s goal of more cures for kidney cancer, with targeted immunotherapy.
QED
Audience: Does the pathway of the targeted drug therapy have any impact on whether or not immunotherapy would have any effect on tumor growth or not? Different targeted therapies have different modes of blocking pathways. Would that have impact, or has your research shown any impact on different pathways.
Mc Dermott: “That is a very good question and not simple to answer. Many of the treatments I talked about, like the cytokines, like IL2 or interferon or CTLA-4 work on the patient’s immune system-we think ONLY, only, meaning they are boosting the immune system to an established cancer. For reasons we don’t completely understand, that is effective in some patients and not in others. In the case of the PD-1 antibodies, they may be acting on the immune system, and may act on the tumor as well. There is some evidence of that in the early research, as I mentioned with patients who have this barbed wire on the surface of their tumors, or have this pathway activated, or when this pathway is on, they may be more likely to respond to this approach. Meaning, when the barbwire is up, and you can block its activity, maybe you can lead to an effective immune response. And what that may say something important about the pathway, but it may also say something about the immune system’s response. The barbed wire, we think, is up, as a reaction, a survival mechanism for some tumors. That is one of the reasons that cancer is so difficult to deal with, that there are so many different ways the tumor can evade the treatments. That barbed wire, that PD-1 may be one of those protection mechanisms. So that means tumor turns on, the barbed wire is up when the immune system is there, you can’t kill it, but you can block the barbed wire, take these immune cells are right there and it can kill the cancer. This may explain why some patients have a benefit and some don’t. And we are now looking to see, if your tumor has barbed wire, whether you are more likely to respond to treatment. There will be a lot more information about that in the future. Good Question.”
Question: I wonder if you knew if there was a clinical trial going on for prostate cancer, believe it is called XPl 4(sic), and its for bone mets, and if you knew anything about it’s work with RCC.
McDermott: “Re this med and RCC,I don’t treat prostate cancer, just melanoma and kidney cancer. Is the drug you are talking about XL 184? This is a drug that is in early trials, and maybe Dr. Jonasch will talk about it and similar drugs. These drugs work in the blood vessels to attack the cancer. They target two proteins, VEGF, which you’ll hear a lot about, and another protein which is important, C-MET, called MET inhibitors. There has been interesting activity in prostate cancer with this drug in trial, and a very small trial we participated in Boston with this agent with kidney cancer patients. You will see more info on this drug at the ASCO meeting in June and the info will be public on May 16. ASCO publishes all its info, so you will be able to get your hands on the results from that very small trial in a very few weeks, which is good. It’s a drug that has promise, but it has some side effects that need to be managed. The fundamental question here is for the kidney cancer advocacy community, is it going to be tested in kidney cancer? We are still not definite yet, but we are pushing to test this class of drugs in kidney cancer, this particular drug. We are pushing sponsors to do trials, but they are most interested in prostate cancer. When those trials are to start and with kidney cancer, we are not entirely clear. We need to push them to keep developing these interesting drugs for our patients.”
ME: This is an extension of the question, as to how you choose the best patients who have the best chance of responding to IL2. Does the histology or the pathology, and frankly I don’t know the difference between the two, have a major impact, and can you expand on that?
McDermott: “Yes, I may have gone too quickly on that. We thought the answer was yes, and when it comes to big differences, clear cell versus non=clear cell, it does, meaning when patients come to us, non-clear cell cancer for IL2, we will say to them, ‘It’s not going to help you, or the chances are so small, that the harm or potential harm outweighs the help.’ So to answer one of your questions, non-clear cell histology, which is simply a medical term for ‘What does this thing look like under the microscope?’.
For non-clear cell histologies, we don’t offer IL2. Whether one of these newer immune therapies work for that class of patients, should be tested because there is hope. That is why I mention the lung cancer story, because if it can work in lung cancer, it might in one of these less common kidney cancer types. It may work for many other forms of cancer. So that is a hopeful thing and exciting. But to take it a step further, while we thought clear cell cancer was more likely to benefit, we also thought it was that certain types of clear cell cancer were likely to benefit. That is what we tried to prove in that trial, but we couldn’t prove it. Doesn’t mean it wasn’t so, we just couldn’t prove it. We haven’t improved out selection ability based on looking under the microscope in ways that we had hoped. We can do it a little bit, and that’s why the response rate went from 14% when the drug was approved to 25 % today, but it’s not enough, so patients don’t have to go through the side effects if they are not to benefit from the treatment.”
Question; I don’t know if I know enough to ask a coherent question, but this is related. Why would it be that certain tumor types or subtypes would respond to IL2 or not? Is it because their profile of cell surface markers that let the immune system targets them better?
McDermott: “That’s actually a very sophisticated question, and one that does not have a clear answer. It may be, one thing you mentioned, it may be that the immune system usually recognized proteins, usually proteins associated with infections like viruses or bacteria. So it may be, as you point, that there are certain tumors that have show these proteins to the immune system better than others. And then the immune system can detect these proteins and say, “This is something wrong here, let’s go kill it”. That’s one possibility, and we tried to prove that in our trial, because one of the proteins we looked at was the protein called carbonic anhydrase IX. We thought this protein was being recognized by the immune system and that might predict for benefit, but we couldn’t prove it. So many people suggested your theory, which was that these proteins are important, but we could not prove it in this trial. It doesn’t mean that there aren’t others that are important, we just couldn’t confirm it. It may also mean that there are certain aspects of the tumor, that even though it is recognized by the tumor, something is preventing it from dying under the strain of an immune attack. That has to do with how well a cancer cell dies under stress. There may be some that don’t automatically shut down when they are being surrounded, that’s part of it. There are also other important proteins that the tumor can make to avoid detection so the opposite of what you are talking about, that barbed wire analogy. These are proteins that the tumor can turn on, and act like barbed wire, so that when the cells are coming it, they are turned off. So there’s a variety of different theories and more than one aspect of that. It’s a fairly complicated story.”
Me; Back to CA IX, the fact that you expected that more of that would lead to greater response, you found the opposite to be true?
“No, we didn’t find the opposite to be true, we found that the folks who had CA IX protein on their tumors did well, or better than the old numbers. Those patients responded at about the 25%, but they did as good anyone. What was different was that the patients who didn’t have CA IX on their tumor did just as well. So that is why I said it was bad for the research, but good for those patients. We would have assumed, if we hadn’t done the trial, that to those patients, we might have said, ‘You don’t have CA IX on your tumor, no IL2.’ We did the trial to show that, we couldn’t. That means that going forward,, we should include those patients getting IL2.”
Me: I went on IL2, and I am a complete responder, and I had a relatively low level of CA IX, so I always watch that and wonder.
McDermott: “You are an example of why my research career is floundering,” laughing.
Me; Sorry, but it works for me, works for me!
McDermott: “I am very happy for you and for those patients on the trial. That is why you do the research. The CA IX story, and this was scary when I saw it, actually made it into the medical training literature. So if you were an oncology fellow, you learned that McDermott at Beth Israel and others said CA IX was important, and that high CA IX patients should IL2 .And then when I saw the results of the trial, I thought, O my gosh, this has become gospel, and is maybe not right. You are a perfect example of it, and it means we need to do more research into the area . You are an excellent plant could not have been better.”
Audience: Did you say that you have some non-clear cell patients on the MDX trials?
“Not yet. Most of them whose tumor type we knew all have been clear cell. But in some of the future trials there are small numbers of non-clear cell patients who will be enrolled. If there is any sense of activity, it may encourage study sponsors/drug companies to develop it in non- clear cell patients. They will not be excluded on trials going forward.”
Audience: So you your knowledge there is not one which is limited (to non-clear cell) for MDX 186?
“I haven’t seen a response in that category, since most of the patients are clear cell the assumption in the field is that clear cell benefits from immunotherapy, so when you try to prove a principal, they try to collect the patients most likely to benefit, so not to put people through treatment that will not benefit. But now that we have this proven—really not proven—but a hint of effectiveness, different types of patients are being included in the trial. For example, the trial which includes the addition of MDX agent with Sutent allows non-clear cell patients. Hopefully there will be more of those in the future. The good news is there is more than one drug company developing these antibodies, and I will include those in my talk this afternoon.
We don’t do all the work at our place, but I haven’t seen a non-clear cell responder at my place. I have seen responses with very aggressive tumors, that had sarcomatoid features, for example, but I haven’t seen one with non-clear cell. That does not mean that it has not occurred.”
“Little about adjacent organ invasion. Most times when kidney cancer grows, it pushes things away. It rarely invades the liver, the colon, but if so, it is a really bad sign. Where there is locally advanced disease, with local organ invasion, those patients do the worst.
One of the challenges as a surgeon when the patient presents with local organ invasion in a CT scan is to determine if it truly exists. If we truly could identity those patients with local organ invasion, we might refer them for systemic treatment with a targeted agent before doing surgery.
We had 53 patients who had evidence on CT scans of adjacent organ invasion, but 30 did not have metastatic disease and 23 did have metastatic disease. Since 38% of those patients did not have adjacent organ invasion, what does that tell you?
That tells you that CT scans and MRIs are not the be all and end all of surgical planning. Those images are wrong 40% of the time. we were wrong, and if we doomed those patients not to get surgical treatment, and go on to get systemic treatment, it makes me wonder what their outcome would have been.
slide 51
This graph demonstrates that patients who have organ invasion do bad. In the absence of metastatic disease the median survival was 2 years and with metastatic disease the patients were dead within six months.
Slide 52 These are big operations, median blood loss of 2 ½ liters. Like to point that the big blood loss was not my case! But we do see complications with a mortality rate that is acceptable, so we can get patients through the surgery, but it is a big surgery
Slide 56a
:Again, the factors that predicted outcome for this group — patients who did not have true organ invasion, and again that feature that predicts outcome, presence of node metastases.
Renal Fossa Recurrence
Slide 56a
I will finish up with renal fossa recurrence. That means, after the tumor is removed, the patient recovers, the tumor grows back in the same place where the kidney was.
This retrospective study we did at MD Anderson seven years ago looked at 16 patients with locally recurrent RCC. Eight received neoadjuvant therapy and 7 received additional adjuvant treatment after surgery. Of the group of eight with neoadjuvant therapy, 50% were NED. The surgery alone group only 25% were NED, which shows a combination approach, that some form of therapy plus surgery is better than surgery alone.
Slide 58:A study out of Mayo Clinic basically shows the same thing. Patients who received surgery and systemic therapy did significantly better than those that received systemic therapy alone.
Slide 58: We recently published our study of renal fossa recurrence. We identified 54 patients who present with local recurrence, 69% of these patients received some sort of peri -operative systemic therapy. They all underwent surgical resection.
Slide 59: Again, this is a relatively aggressive form of RCC, with the occurrence free survival of about a year, but with aggressive surgical resection, these patients can live a long time. The median cancer-specific survival was more than five years.
Slide 60:
We tried to identify which features predicted outcome and found that those patients whose tumor size was less than 5 cm, and the ability to get a negative margin,meaning to remove the entire tumor with surgery– the absence of sarcomatoid features, a normal level of LDH in the blood test and a normal alkaline phosphatase, blood tests that we get; all these features predict outcome.
Nowadays when someone presents with a local renal fossa recurrence, we look at these features to see whether or not they are a good candidate for surgery, or if we should refer them to our medical oncologists for additional treatment.
Slide 62 is incomplete/ Wood’s comments follow: In summary, aggressive surgical resection, when feasible, still remains the best treatment for renalcell cancer. The role of targeted therapy agents in the adjuvant and neoadjuvant setting is unknown and should be protocol driven. Management of locally advanced disease remains a surgical challenge, but when done properly and by experienced surgeons, can give excellent outcomes.”
Surgical Management of Locally Advanced Renal Cell Carcinoma Part 3 of 4
Budd-Chiari Syndrome & Nodal Disease
One devastating complications of venous tumor thrombi is the Budd-Chiari Syndome. The thrombus gets so big that it plugs up the vein, plugs up venous outflow from the liver. Patients present with abdominal pain, ascites, i.e., fluid in the abdomen, edema of lower extremities, enlarged liver, and their liver function tests are all abnormal.
If we take these patients to the operating room, the mortality rate is about 80%. Because of this we no longer take these patients to the OR Instead we will embolize the tumor, cutting off flow of the blood to the tumor. For those patients that regress, we will take them to surgery and they do well.
It is not a very common presentation; we had six patients, two of whom were without evidence of disease after 3 years, using this approach.
NODAL DISEASE
There is a study where patients with localized RCC were randomized to either node dissection or not– to look to see if node dissection improved outcome. This trial showed that patients who had no dissection did no better than those who did not have node dissection. Many will use this in urology community to say that patients who have kidney cancer do not need to undergo node dissection in the absence of metastatic disease.
In a more recent update on this, again, those patients who had a node dissection did no better than those with a node dissection.
But one thing about this trial that troubles me and many in the urologic community is the significant percentage of patients who had very low stage disease. So it gets to the discussion of risk. If you study what you are doing in a low risk population where the frequency of the percent of expected adverse event is so small, you will never see a difference. The problem with this trial is that they need to focus on more advanced stage disease to see if node dissection really makes a difference with kidneycancer.
The group at Mayo did some very elegant studies which showed us where the positive nodes are. So now we go in and do a node dissection on a patient with locally advanced tumor, and we have a very defined area where we know the highest likelihood of metastatic disease is to occur. If we took out all the nodes, the complications would be enormous. We now are directed in where we go looking for nodes and remove them in that fashion.
Side 37 : The group at UCLA did a retrospective study and noted that if you did not have enlarged nodes, it did not matter if you took them out or not. Again, like the EORTC trial, but critics of this argue that it presents low stage disease. But one of the interesting things that did notice that in the patients with positive nodes, that if you took those nodes out they did significantly better. Indicating, even in the absence of systemic treatment, surgery could influence the biology of the tumor.
Slide 38
The group from Mayo identified features that predicted for positive nodes. These include high nuclear grade, the presence of sarcomatoid histology, large tumors or more advanced tumors, or the presence of tumor necrosis.
38a They assessed the primary tumor when it came out of the patient, and if there were 2 or 3 of these features, the risk of having nodal disease was significantly high that they triggered a node dissection. Now they use this prospectively to see if this does let us give better outcomes. This may give us the ability to predict who likely has positive nodes and therefore should undergo a node dissection.
Slide 39 This was a study that was done some years back, but it intrigued me. In patients that had even met and positive nodes, for example, mets to the lungs and positive nodes. Those patients do significantly worse in their prognosis than those without positive nodes. This suggests some adverse biology that is associated with positive node involved.
They also noted that if they could just dissect those nodes, again even in the presence of metastatic disease, they did significantly better than those whose nodes were left in place.
This is a study out of UCLA which shows that patients with metastatic disease do worse in the presence of positive nodes.
Slide 41a We recently looked at our experience (MDACC) with patients with metastatic RCC and positive nodes, limited to clear cell histology. We had 55 with positive nodes compared to 322 who did not. What we noted that those who present with positive nodes do worse than if they do not have them.
Slide 41b But you can see that if they undergo lymph node dissection, even in setting of metastatic disease, they did significantly better, almost a doubling of their survival as patients who did not.
Cytoreductive Surgery Prior to Systemic Therapy for Metastatic RCC
Slide 41c If patients do present with positive nodes, we aggressively resect them, as it significantly impacts on their ability to get treatment. So nowadays, when patients present for cytoreductive nephrectomies, if they have positive nodes, we aggressively resect them, as it significantly impacts their outcome, and their ability to go and get treatment.
Role of Aggressive Surgical Resection in Patients with Positive Nodes in the Absence of Distant Metastases
What about those patients that don’t have metastatic disease but just positive nodes. How do those patients do? We recently looked at our series of patients with positive nodes in the absence of distant metastases, and wanted to asses what factors predicted what affected outcome.
Slide 41d
Out of 3201 nephrectomies, we identified 2521 who did not have metastatic disease, and of those 68 had positive nodes. Surprisingly, we found, that in positive nodes–that the tumor has left the kidney and metastasized–and surgical patients still do pretty well.
Slide 42: There overall survival rate at five years is 37%. You might say, that is pretty low, but that is with surgery alone. But disease specific survival is 39% at five years.
slide44: But when disease recurs, it generally recurs early, at within the first year, but more than a third recur greater than a year out.
Slide 44a: And when patients do recur after this surgery, they usually recur in multiple places with metastatic disease.
Slide45
We wanted to look at factors that predicted for outcomes in these patients. So these are these are the demographics, (editor’s note; the video does not include these charts and slide, which are from the original, unedited video) the vast majority had good performance status, they had local disease, confined to the primary tumor and the overwhelming majority had clinically positive disease. This was not microscopic disease, rather big nodes you can see on CT scans.
What we noted, interestingly, in terms as predictors of overall survival those patients with papillaryhistology had a significantly better outcome, than those with clear cell histology. Those with only one node had a significantly better outcome than those with more than one mode.
When we looked at time to recurrence, again, papillary histology seemed to be a predictor of who would do well. So patients with papillary histology and positive node involvement, we will aggressively resect them.
Slide 45: The multi-variate analysis predicts for overall survival, and papillary histology, the number of nodes positive involved, the presence of sarcomatoid features and status all predicted outcome.
Regards of the time to recurrence, only the number of nodes involved and tumor grade were predictive of outcome in these patients.
(Slides are variations of the same information.)
Secondary Treatments
What about adjuvant therapy in these patients? I already told you that adjuvant therapy doesn’t work. In this particular group, 5 got adjuvant ttreatment and in those 4 patients, it recurred. The important thing is that 85% of these patients had good performance status at three months. What does this say? It means we can do an aggressive surgical resection and patients bounce back very quickly. If they need to go on to get additional treatment, even after this very large surgery.
So these are the feature that predict outcome; papillary histology, number of nodes, sarcomatoid features and ECOG performance status.
I will continue with “Adjacent Organ Invasion” in the next part of the lecture.
Surgical Management of Locally Advanced Renal Cell Carcinoma
Next is the management of more advanced disease, in patients who present with tumor thrombi, nodal metastases, adjacent organ invasion and renal fossa recurrence.
The first is venous tumor thrombi. This is one of the biggest operations that I do, as about 15% present with venous thrombi from their kidney cancer. These can be huge. This can be very complicated, as these thrombi can go up into the heart. We then have to put these patients on by-pass, open up their chests, stop their hearts and put them on a bypass, so we can take the thrombus out. We use TransEsophagealEchocardiogophy to monitor of the thrombus, to make sure that the thrombus does not break off.
This is a series that we recently published at MD Anderson, 605 patients with venous involvement, median age of 60 years, follow up of 24 months. 45% had no evidence of metastatic disease; conversely 55% obviously had advanced disease. The more advanced stage, the higher the risk of metastatic disease.
These are big operations; median blood loss is a liter and length of time is 3 hours, with complications inthe first 30 days for 25% of patients. Patients stay in hospital about six days. But even with venous involvement up to the heart, in the absence of metastatic disease, there is a median survival of five years, so even these patients can be cured with surgery alone. But once they demonstrate evidence metastatic disease, survival drops off dramatically.
Predictors of Overall Survival Slide
We looked at a variety of different parameters, won’t bore you with all the details. We looked to see what predictor survival for these patients and this is what we found.
Those patients who had clear cell histology actually had a more favorable outcome than those with non-clear cell. Those who had advanced grade, sarcomatoid de-differentiation, those who had peri-nephrectic fat, nodal metastases, distant metastases, all were associated with a more adverse outcome than patients with venous thrombus involvement.
Interesting was in our studies, not shown elsewhere in the literature, is that the height of the thrombus in the vena cava did not seem to matter. In other words if it was only in the renal vein, versus in the vena cava and that is at odds with the literature that is out there. It only seemed to matter when it went up into the heart, the red line at the bottom and with that, we saw a decrease in overall survival.
Tumor Thrombus and Survival
Our series are in concert with others, in regards to survival in the absence of metastatic disease that patients can have a long term durable survival, with about 60% with five year disease-free survival
Microscopic Positive Vein Margins Associated with Increased Local Recurrence & Metastatic Progression
One of the other things we noticed from our series that made me wake up was the concept of the vein margin. Of 270 patients, who had no evidence of metastatic disease, almost 20% of patients had cancer present at the margin of resection. When we resect the vena cava, we are obviously limited in how much we can take, unless we are doing a reconstruction, which is really fraught with complication.
(associated with increased metastatic progression.
But those with a positive margins, meaning they had cancer sitting at the edge of resection, where we cut the vein, had a greater risk of local recurrence, a higher Fuhrman grade. Those patients had a worse outcome, not surprisingly.
So now when we do these surgeries, we send the resection for a frozen section to be sure there is no cancer at the margin. If there is cancer at the margins, then we will do a reconstruction to try to reconstruct the vena cava to try to eliminate all the cancer.
Also in the literature that is out there that is a bit at odd with our series; here they noted that patients who had only renal vein involvement had significantly better outcome than those who had IVC (Inferior Vena Cava) involvement. There is some data that suggests that the height of the tumor in the vein is somehow related to outcome but that is not what we are seeing in our patients.
In this series, IVC (inferior vena cava) wall invasion, tumor size, fat invasion, nodal metastases, and distant metastases all were associated with an adverse outcome in patients with venous tumor thrombi.”
Dr. Wood continues his discussion of surgical management of “Locally Advanced Renal Cell Carcinoma” with Budd-Chiari Syndrome in Part 3.
Dr. Christopher Wood, of MD Anderson Cancer Center lectured at an April 2012t KCA patient conference on this critical subject. It is a technical discussion, highly important for the patient whose kidney cancer is not longer consider “small and curable” by surgery alone. For greater ease in following this, I have posted this in four segments. My comments will follow in a separate blogs. My hope is that the information is meaningful, so that a patient can learn enough to have a discussion with his/her doctor. Print out the information you have read and give it to the doctor to start that discussion. Some slides were principally text, so I have recreated some to keep the file size down; anything which was not readily converted to text remains as the best available slide.
Consider saying to your doctor, “Here’s what I have been learning, doctor. How does that fit into our plan for my treatment?” That tells your doctor know you are willing to learn and to listen, and to take an active role in your treatment decisions. Unless your doctor deals daily with many kidney cancer patients, he is unlikely to be able to keep up with all the information, ever changing, and ever more complex, about your disease. If the doctor is not willing to listen and learn from the leaders in the field…find another doctor.
Peggy: RCC Patient, Stage IV mRCC 2004; healthy today, thanks to HD IL2
“Outcomes for Patients with Locally Advanced Renal Cell Carcinoma”
Dr. Wood begins: “My first lecture is “The Management of Locally Advanced Renal Cell Carcinoma”. Slide 1
Stage is the most important predictor of outcome: the more advanced the stage, the greater risk that the tumor has spread, with distant metastases, making the disease incurable.
This is the staging system we use in 2012, where we stage tumors, assess regional lymph node involvement and look for evidence of metastatic disease. People get hung up on their staging, but this allows doctors to communicate about patients in the same language about how advanced one tumor is. With increasing stage, there is a more locally advanced tumor or metastatic disease.
Let us start with definitions. (Reads slides 2 & 3)
Adjuvant Therapy means some form of therapy– chemo, radiation, vaccine, whatever–after complete surgical tumor resection with the idea to decrease the risk of recurrence of disease. The benefit is that the patient has already had surgery before getting additional therapy, but the downside is that many of those patients may have been cured by the surgery and they may get treatment they don’t really need.
Neoadjuvant therapy is taking some form of therapy, whether chemotherapy, radiation, vaccine, etc. prior to surgery to the primary tumor in hopes the tumor may decrease in size, and decrease the risk of recurrence. The benefit is it may allow the tumor to shrink and make surgery easier. The downside is that the therapy may not be effective and not inhibit metastases, and the primary tumor would not regress, but progress during therapy.
Slide 4
Effective adjuvant or neoadjuvant therapy does not exist for kidney cancer in 2012
Any therapy must be developed in the context of a clinical trial setting, and including a placebo. The only way we make advances is to test what we do now with any advance in the future. And what we now know, as I said, is nothing.Patients have a hard time, with placebo trials. If you participate in such a trial, the treatment you are getting may not be good and the placebo arm, not so bad.
Slide 5 Who should get these therapies? Why not give them to everyone? Anyone taking the targeted therapies today knows the toxicity is significant, and you may treat a significant number of people who really don’t need the therapy. Then if nothing works, why not give it to anyone? Well, we are never going to make advances that way, so it is important that we continue to do research and focus on those who are highest risk for relapse. Should we give it only to those at a highest risk for recurrence? The difficulty how do we define risk, how high is high? So it’s not really clear.
Adjuvant Therapy: 2012
A variety of trials have been performed. Many patients have participated. They include radiation, embolization, energy ablation, a variety of different hormonal therapies, immunotherapies with interferon and interleukin 2, all having been used in an adjuvant setting. There have been a variety of vaccines preparations and we did a Phase III trial of thalidomide trial here. To date, not one ofthese therapies has shown benefit in the adjuvant setting. In fact, many of the patients on the treatment arms did worse than those who were not treated.
Slide 7 What about targeted therapies? That is also the great unknown where things stand with targeted therapies in the adjuvant setting.
Since 2006 there have been seven new agents against kidney cancer. It’s been a revolution. And to be honest, many have benefited from that advance. How do we use these agents in the context of adjuvant therapy?
Slide 8 There is a variety of trials recently completed or in accrual, ongoing. Tthe ARISER Trial used an antibody called G250 against Carbonic Anhydrase IX, and patients were randomized to get either antibody or placebo. This trial completed accrual many years ago, in fact, and we are still awaiting results which leads me to believe that is probably going to be a negative trial.
But this same agent has recently shown promise for use in PET scans for kidney cancer. You can use this as an imaging agent. The patient is infused with the antibody and linked to item 125, and it will show up on x ray, and may potentially detect micro metastases not visible on CT scans. This is actually undergoing FDA approval.
Slide 10
This is the ASSURE trial we conducted at MD Anderson. It is a randomized, double-blind phase III trial of Sunitinib vs Sorafenib vs Placebo. Patients underwent surgery, then were treated with these agents for 1 year. This trial was completed accrual last September (2011) and we are now waiting for the trial to mature to see whether these agents have any benefit in the adjuvant setting.
Slide 11
One thing that we did learn from this trial is that tolerance for the toxicity associated with targeted therapy in the adjuvant setting is not the same as in the metastatic setting. In this trial 41% of patients stopped therapy early, not because disease returned, or because they finished, but because of toxicity. I think it comes down to an individual assessment of the risks. If I told you that you have a 20% risk of your cancer coming back, versus your 70% chance of your cancer coming back and you are miserable on this therapy, all of a sudden 20% doesn’t look so bad.
My concern about this, because at the end of the day, if this trial matures and it is negative, will it be negative because the agents did not work, or because the patients could not tolerate the side effects. And too many patients stopped the trial early or had dose reductions. I’m afraid it is not going to be interpretable.
Slide 12 This the S-TRAC trial, sponsored by Pfizer, recently completed accrual. It’s randomized between Sunitinib with a placebo for one year. It is estimated results will come out in 2017. That’s the other problem with these trials. Are the agents we are testing now, will they even be relevant in 2017? No one knows.
Slide 13/12
There has been a real problem in accruing to this trial. In fact, we can’t even keep patients on Sorafenib for three years in treatment, never mind adjuvant setting.
Slide 13
This is a trial going on in the US, sponsored by Glaxo-Smith-Kline. This is called the PROTECT trial. Patients are randomized to Pazopanib (Votrient) or placebo for one year. This is primarily open to clear cell patients, here at MD Anderson.
SLIDE 15 A
This is the EVEREST trial, sponsored by the SWOG, going on around the US, with patients randomized to one year of Everolimus (Afinitor) or one year of placebo.
You can see that clinical research is actively ongoing to identify if these agents work in the adjuvant setting. But it is going to take more time to understand from these trials before we know if this is applicable in these setting or as with the other agents, if they remain ineffective.
Slide 16
One other concept we are testing at MD Anderson that I will talk about a bit more in the next talk is a neoadjuvant therapy, testing Axitinib in the neoadjuvant settings. Some in the audience have been on this trial, where patients receive Axitinib for three months and then undergo nephrectomy.
I would like to applaud the patients who participated in this trial. Like to give you an idea how this went the first time we enrolled a patient. Patient comes in with a tumor, curative with surgery, and we say, “We’d like to give you this agent, we don’t know if it will work. In fact, your tumor may grow and metastasize while you are getting this agent. If we took you to surgery tomorrow, we could probably cure you. What do you say?” It was really amazing. The first patient who enrolled in this trial was very brave. But since we have been able to show activity with this agent, enrollment has picked up significantly.”
Dr. Christopher Wood ends the first part of this lecture, with the next section about “The Surgical Management of Locally Advanced Renal Cell Carcinoma.”
The Small Incidental Renal Mass: Treatment Options
I have summarized and edited presentations from an April 2012 Kidney Cancer Association Patient Conference so patients can read and study them.
The original presentations can be found on YouTube offered by the KCA.
Poor resolution slides have been reconstructed
Treatment Options for the Small Incidental Renal Mass
After a brief welcome and expression of appreciation for the KCA, Dr. Karam begins:
“Currently, a small renal mass is defined as smaller than 3 or 4 cm, localized to the kidney, not invasive to other organs. This is a consensus and these definitions can change. Of all Stage I kidney tumors, 43 % are less than 3cm in size. (Some Stage I kidney cancers can be larger than 3cm; other treatments may be more suitable.)
I will discuss three options with patients who present with these types of lesions. The first is active surveillance, the least invasive, the next is energy ablation, and the third is surgical removal. Each will be discussed in the sequence.
First “Active Treatment Options” is energy ablation. This can be done through the skin, percutaneously, laporascopically, or be done “open”. Energy ablation includes two categories, Cryoablation (CA)–freezing the tumor, done laporascopically or through the skin. Alternatively is Radiofrequency Ablation (RFA), typically done percutaneously, or through the skin.
The second major category of active treatment is surgery, the standard of care being an open partial nephrectomy. That removes just the tumor, leaving most of the kidney. It is now more often being done as a robotically assisted partial nephrectomy. Another option is to do it laporascopically, with minimal incisions. Radical nephrectomy, complete removal of the kidney along with the tumor is the lowest on the list. It is the least favorable option, as we try to save the kidney, wherever possible.
AUA (American Urological Association) Guidelines have published some guidelines, based on multiple studies and experts. The standard of care for treatment of small kidney masses is partial nephrectomy. A radical nephrectomy is used only if the mass cannot be removed by partial nephrectomy. A recommendation could be ablation or active surveillance. This will be tailored to individual needs of the patient and the kidney, as to the location of the mass and its characteristics. No one recommendation fits all patients, and each must be discussed and individually tailored.
Next is active surveillance. We don’t use “watchful waiting”, but “Active Surveillance”. We do not to tell someone to go home with your small mass as we don’t need to do anything about it. On the contrary, we have to actively bring the patient to the clinic for CT scans.
What is active surveillance and what does it entail? That means doing no interventions, no surgery, and no procedures that are invasive–active surveillance. Initially we would do imaging at 3-6 months intervals in the first year, subsequently imaging at 6-12 months. There are no rigid guidelines at this point. I always tell my patients to be aware that we have only had small studies with active surveillance, and with short follow-up of 2-3 years. There is a very small potential for spread or metastases while we are doing active surveillance, so every patient has to be informed about all of this.
How often do small masses spread or metastasize? When does it seem to happen? This is a meta analysis of data from 18 studies with almost 900 patients. In only 18 patients of 880 did metastases occur while on active surveillance, a rate of about 2%. This spread occurred almost 3 ½ years after initiation of surveillance, so it does not occur in the first 3-6 months, more on average about 3 ½ years.
“How fast does a mass actually grow?” We know that 23% do not grow at all within 2 years or so. The rest do grow at the growth rate shown.Comparing the growth rate of those who had spread or metastases with those who had none, only 18 patients had spread. The group without spread was typically younger (66 versus 75), with a smaller mass at the initial presentation, 2cm versus 3 cm. The final size in centimeters of those who had spread, those 18 patients, was about 5.9cm. The tumor was quite large at the time when the metastases occurred, and here we started at a size of 3.1 cm.
The growth rate was about 2mm per year for the patients who did not have spread, and about 6mm per year for patients who did have spread. The time on active surveillance was about 2 ½ years.
Of these patients on active surveillance, what happened to them, did they all continue after active surveillance? Over half did remain on active surveillance, over a period of 2-3 years. Fewer than half had delayed intervention. They might have gone to ablation or surgery, and this is over a period of 2-3 years. Others had “delayed intervention, with patients having ablation or surgery on average about two years after starting active surveillance.
The common reason for moving from surveillance to intervention was typically patient concern about the growing mass—patient anxiety. The next reason was enlargement of the mass and the third one was that a patient had some bad medical problem initially not related to the mass. When that problem was solved, and became a good surgical candidate and they are switched to surgery.
Energy Ablation: Radiofrequency
Next is Energy Ablation, a more invasive category which includes radiofrequency and cryoablation.
How does radio frequency ablation work? I usually tell my patients that is basically frying the tumors. The waves from radiofrequency cause friction and movement in the water molecules. This produces heat and destroys the tumor. Cell death occurs in about five minutes after exposure to the RF, with the temperature over 50 degrees Celsius )122 Fahrenheit. This can be monitored during the procedure. We have to achieve temperatures up to 100 (212 F)degrees in order to effectively destroy the tumor with this procedure.
This is a CT scan of the vertebral column and the patient is laying flat on this tummy. This is the kidney, this is the mass, and is CT guided. The interventional radiologist usually puts this thick needle with these tines, typically done under general anesthesia. Though we can do it very infrequently under conscious sedation, but general anesthesia is preferred. A biopsy is typically done at that time and one or more electrodes are inserted. Immediately after the procedure iss done, we do a CT to see that there isn’t any bleeding and to make sure this was treated adequately.
Energy Ablation: Cryolablation
(This is a video which can be seen on the Youtube video.)
The next category of energy ablation is cryoablation or freezing the tumor. This is a picture during laparascopic surgery. You can see them freezing the tumor. This is the kidney here, the tumor here. The tumor here has been marked; the electrodes that go into the tumor, freeze the tumor and form an ice ball.
We use two gases for this procedure. The first is argon, which causes rapid freezing at the tip of the probes, with the temperature dropping to less than 80 degrees Celsius. The second gas is helium, which releases heat as it depressurizes, and it causes very fast thawing of the tumor. This typically repeated twice, two cycles of freezing and thawing. Multiple probes can be used to achieve tumor ablation. With this technique the ice ball can be monitored and you can see the progress with time. This can be monitored by CT or MRI, done percutaneously under guidance, or with an ultrasound when you are doing it laporascopically. or with an ultrasound when you are doing it laporascopically.
Cryoablation—How Does It work?
The Cyroablation acts directly on the tumor cells. It dehydrates the cancer cells, removes all the water from them, which causes damage to the enzymes which are needed for survival by the cells, the organelles and the cell membranes. It also causes the formation of ice inside the cell and kills the cell. But it can also act indirectly, as it targets the cells directly, cutting off nutrition needed for growth. In order to achieve this, very low temperature have to be reached, and to achieve it homogeneously for all of the tumor, the ice ball must extend ½ to 1 cm beyond the margin of tumor to make sure it is completely frozen.
Cryoablation
As to follow up, how do we know it is still working? There will be routine visits to the clinic with medical history, physical exams, chest imaging which is either with conventional radiography, CT and routine blood work.
Follow Up
To follow up on the tumor itself, we typically do a CT or MRI with IV contrast to visualize the tumor. The first follow up is at 6 weeks after the ablation to make sure the ablation was complete and successful and then at 6, 12, 18 and 24 months after ablation.
It does not mean that follow up will end at 24 months. The patient continues with scans for life, routinely, at least once a year after deletion or the treated tumor is stable. So imaging has to continue for years, as we don’t have long term studies with these technologies.
We tend to do more biopsies if the mass is not shrinking well enough, or if it is taking contrast, or it doesn’t look right one year. If the mass is not looking right, we go ahead and do the biopsy to make sure there isn’t any recurrence.
Recurrence defined after ablation can be tricky because the mass is still there. A successful ablation is defined as lack of enhancement of the tumor with the use of contrast. That is why is it very important for the patient to receive and tolerate contrast IV contrast for follow up after ablation. With cryoablation, typically you see tumors shrinking. With Radio Frequency, it doesn’t always happen. That is what makes it trickier, so we have to do biopsies for patients after treatment. And again, the tumor does not always shrink; more typically it does with the cryoablations. Again, radio frequency ablation lesions don’t always shrink, so absence of enhancement is what we look for which is not always ideal.
Now we always discuss with our patients the potential need for biopsy after ablation so this may be expected, though is not routine. Thus, the patient has to be aware of this. We don’t do it routinely, but it is a possibility.
What can predict who is going to have a successful ablation? Tumor size less than 3 or 4 cms is a very good indicator that we will be able to successfully ablate the tumor. If the tumor is exophytic, that the tumor is not deep into the kidney, this is a good indicator. If the tumor is peripheral or not central, that means that the tumor is away from the artery and the vein of the kidney. This is also a very good indicator that we can successfully treat it with ablation.
There are some complications, including pain after the procedure. This is usually an overnight stay; the patient goes home the next day. There could be some numbness or neuromuscular complications. There can be some air around the lung, if the needle had to be inserted close to the lung. This is typically monitored during the procedure.
Seeding from the tumor is exceedingly rare, maybe 1 or 2 cases, so exceedingly rare, nearly unheard of, so this should not be a concern for patients who are willing to go through this procedure. Bleeding can occur, and that‘s why we like to keep patients overnight. Also there could be some strictures or narrowing of the ureter tube that drains the kidney.
So how do we know to recommend RFA or Cryoablation?
We know RFA is considered easier, faster, and safer, but actually has a higher chance of doing damage to the collecting system, the system that drains urine from the kidney. On the other hand, CA has a slightly higher risk of bleeding compared to RF. But it is better for larger tumors, and is good for deep tumors or central tumors. You can monitor live CA with ultrasound or CT to see the ice ball actually grow and treat the whole tumor.
Partial Nephrectomy
The more invasive category is the partial nephrectomy, the actual removal of the tumor, leaving the rest of the kidney in place. The standard had been the open procedure, but nowadays, people tend to do more robotic assisted surgery. You have to have a good surgical candidate for this, both as to the patient’s anatomy and the actual mass. Less commonly used is the pure laparoscopic, just because it is technically challenging and because most hospitals have a robot available.
(VIDEO available on Youtube, about 17 minutes into clip.)
We will show a two minute clip of robotic nephrectomy surgery, courtesy of my colleague. The kidney is here, artery to the kidney here and the vein to the kidney is here. First we need to stop the blood flow to the kidney to do this procedure safely and accurately. A clamp is temporarily placed on the artery and another clamp on the vein, which will completely shut off the blood supply. Here the tumor is literally being carved out of the kidney. Here is the tumor, this is normal kidney, this is tumor, and this is the tumor over here, normal kidney here, so this is what is considered a partial nephrectomy. We check that the mass is excised and then suture the kidney so we can get normal control and prevent bleeding. All you see here is normal kidney. (This is on slightly fast forward–we don’t typically work this fast!)
So now they are bringing back the edges of the kidney together. We use some substance to prevent bleeding which will dissolve on their own: bringing the edges of the kidney back together. And you can see very early on that very little of the normal kidney is removed, just to give a margin to assure that we remove the whole tumor. We remove all the clamps to bring back normal blood supply to the kidney, so this is how the kidney looks. It is pink because it has the normal blood supply. There is no bleeding seen.
Complications might occur in some procedures. This is a large study of almost 500 robotic-assisted partial nephrectomies. Tumor sizes were about 3 cm, so small kidney masses. The total complication rate is about 16%. Complication rates include everything, even slight fevers, so higher than you would expect. Less than 2% of the complications happen during the surgery; most of the complications happen afterwards. About 99% of the surgeries were completed with a robot. Main complications specific to a robotic–assisted partial nephrectomy are bleeding, urinary leakage (1.7%), radical nephrectomy (1.6%), which means removing the whole kidney.
Bleeding occurred in two patients only during the operation, and about 5% of patients while they are still in the hospital. The treatment is relatively simple. Blood transfusion took care of 4% of these patients. About 2% of these patients needed selective embolization, a procedure that is usually done by interventional radiology and done under sedation. This saves the kidney and controls the bleeding as well.
Urinary leakage is found in less than 2%, with treatment typically to put in a stent or a drain or leaving the catheter in longer. None of these patients needed repeat operations or removal of the kidney.
Another complication is conversion to a radical nephrectomy, which occurred in less than 1.6% of patients. This may be due to finding multiple tumors not recognized earlier. In one patient, the tumor could not be found; this happens if the tumor is small and very deep into the kidney. In five patients, a negative margin could not be achieved. That means some cancer was left behind after the tumor was carved out. Then the physician decided to remove the whole kidney to make sure all the cancer was gone. Also, one or more tumors cannot be removed successfully with the kidney left in place. Such complications occur less than 10% under any procedure.
In this table (which could not be captured), but the tumor size was about 3 cm on average. Surgery time was about 3 hours. Blood loss was about 200-300 ccs and hospital stay was about 3 days. This is a different study with complications about 5%. And with positive margins, i.e, a tiny amount of cancer was left, was about 1.6%. The follow up was about four years.
Complications after Treatment Now to compare the rate of complication with RF and cyroablations and surgery: this is from the AUA guidelines; the complication with Cryoablation is about 5%, with RFA about 6%, about 9% with lap partial, and about 6% with open partial and about 3% with complete removal laporascopically, and about 1% with open. All are less than 10% complications.
What about survival without a local recurrence?For cryoablation, it is 90% This is not complete survival, this is living without a recurrence. Again, 90% with cryolablation, with RFA about 87%, and with surgery about 98%.
Renal Function
Partial nephrectomy and RFA has similar renal functional outcomes
No change in GFR
No change in CKD stage
Kidney function is pretty much the same after these procedures, whether you do a partial removal of the tumor or an ablation, so that is not a major factor in decisions.
Active surveillance should be offered to appropriate patients. Patients should be informed that metastases could happen, but typically less than 2% of the time, and it typically takes on average 3-4 years on average. before that would happen. Half of all patients will undergo some treatment eventually, and leave active surveillance.
Survival without Local Recurrence
With the second modality, energy ablation with radio frequency or cryoablation, the chances of survival without local recurrence are about 88-90%, and we have intermediate term data, but not long term follow up on those patients.
However, with surgery you have 98% chance of survival without having a local recurrence to that same kidney. With surgery, we do have long term data as to partial nephrectomy.
A partial nephrectomy is the most definitive therapy. Any patient who is willing to undergo surgery and can tolerate surgery should do have partial nephrectomy for small renal masses. Alternatively, we can offer patients surveillance or ablation. We typically reserve that for that for those with poor kidney function—and we don’t to cause more kidney dysfunction, for those with more have multiple tumors, or for the patient at a high surgical risk or with a poor performance status. That latter patient means he might be a poor surgical candidate due to other health issues, with a heart problem or more dangerous tumors, for example. We can offer surveillance or ablation for those patients. If patient does not want surgery, we can offer two other options. This concludes my talk and I welcome questions.”
The topic “Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer” is near to my heart and in active research at MD A
d they have to move on to the next treatment.
These are two randomized trials, one in the US, the other in Europe, which demonstrate the benefit of patients undergoing cytoreductive surgery. The first is the EORTC trial where patients were randomized to upfront surgery fo
llowed by interferon, or by interferon alone.
trial. Patients are randomized to an upfront nephrectomy followed by Sunitinib versus Sunitinib alone. It is a non inferiority study design, and the randomization is 576 patients. There is a problem; the trial is not at all accruing very well. Patients don’t like to have surgery randomized, with a computer saying, “You’re going to have surgery, and you are not”.
ney in the presence of metastatic disease is beneficial, from retrospective data derived from the expanded access trial with Sunitinib. These patients had their
Patients who had their tumor out had a much better response rate than those treated with their tumors in place. 
