Category Archives: Surgery

“Predicting Short Survival” article: A Self-fulfilling Prophecy for the Newly Diagnosed

I thought I had seen enough articles which concentrated on the stats of how poorly kidney cancer patients did, but then, this one came along from Norway.  “A Three-Variable Model Predicts Short Survival in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma”, just published in 2017, it is shocking and may create barriers to proper care for patients.  The title might have been more accurately titled something like, “How We Fail to Find Kidney Cancer, Therefore Dooming Many to an Unnecessarily Efficient Death”.

Maybe it especially bothers me, in that I have come to expect more of the several Scandinavian health system as I understood them. Also, that I am 1/4 Norwegian, it seems a personal affront.  To lay the ground work, I shall remind you that kidney cancer is often found in the ‘6th” decade of life, or in the 50s, 60s and 70s, most often.  (Any earlier, and there might be a genetic problem, by the way.)  But it is also slow-growing, often can do so without many overt symptoms, but there are often hints.  Of course, if you do not look for those symptoms and search out those causes, you get that slow-growing cancer to establish itself quite thoroughly!  You know the rest of the story, no doubt.

The facts are as follows.  Norway is generally sparsely populated, having about 5.2 million people, with an aging populations, with about 11% over age 70 at present.  There were about 814 cases of kidney cancer in 2014, and more to more, per the stats.  The background statement of the above study notes that it is “important to have realistic perspectives, especially if the expected prognosis is very unfavorable”.  Already I am wondering how expectations by the doctors affect the care they are about to give the newly diagnosed.

In one small area of Norway, Norland data was collected about all newly diagnosed patients, with the stated concern that in trying to select the “best treatment option for an individual, the poor prognosis groups is the most challenging one because aggressive approaches may result in serious side effects in these often frail patients.”  Thus, the researchers wanted to find out how those patients treated within the national guidelines failed.

A central measure of their expectations–no doubt built on the previous years’ patient responses–was the definition of “short survival”, i.e., after the initial diagnosis.  Short survival was for 3.5 months or less…yet the concern from above is in regard to the ‘serious side effects’ in these patients.  Dying within 3.5 months of diagnosis in a modern health care system seems a pretty serious side effect as well!  In this small area there were 48 patients identified in this recent study, 10 of whom died within 3,5 months.  Those 38 patients who lived four months or longer were deemed to have had long survival.  Obviously those patient who were doing badly at the time of diagnosis seemed to die  more quickly.  This seems at odds with the American experience, with much long general overall survival, but it is hard to get those stats, as the US measurements are in terms of YEARS of survival.  A metastatic kidney cancer patient is a Stage IV patient, with the 5 YEAR survival at 8%, per the American Cancer Society–whose stats are necessarily behind the times.  They modify that to note that low-risk patients have a 41% survival rate, intermediate risk patients have a 18% survival rate, and the high-risk patients have the 8% survival rate at five years.

Why such a difference?  The disease is similarly divided 2 to 1, male to female, and there is a near-similar mix of subtypes, such as clear cell, papillary and chromophobe.  The median age at time of diagnosis is 68, slightly higher than in the US. However, in the US, only about 30% of patients are found to be metastatic at time of diagnosis, but in this small study, 70% were found to be with metastatic disease upon diagnosis or within 3 month of that time.  Most important is to note that only 65% of patients in this study were given a nephrectomy, either full or partial.  And post diagnosis, only about 56% of those patients received any systemic treatment.

That seems enough to tell me that these patients were treated very differently that most US patients in terms of surgery, but other statistics were striking. Though the 60-69 age group represented 58% of the patients, only 3.3% were found under 60 years of age.  Was nobody looking for cancer in this group? Imaging for other diseases often reveals kidney cancer, so the 3.3% seemed off the statistical mark.

Only 30% were found to be in ECOG Performance status 0-1, with 70% already struggling with the effects of their disease. Another measure indicates that only 18% had good performance status.  This causes me to wonder how long those patients struggled as well to get a necessary imaging study to verify the presence of a kidney tumor.  (Only 65% of those got the darn things removed!)

Over 55% of all these patients had low hemoglobin, one of the simplest measures found in every blood test.  A pretty good clue that something very fundamental was amiss with these patients. In the group who died within the ‘short survival’ period of  three months, 50% of them had SKIN metastases.  Again, a very visible symptom, and hard to ignore when found with the low hemoglobin.

So how did they do in terms of median Overall Survival?  That was only 13.2 months, and with a 2 year survival rate of 40%.

Perhaps late to be diagnosed, with far fewer nephrectomies than in the US, and with far fewer systemic therapies applied post the time of diagnosis–no wonder the outcomes are so poor! Does this influence the doctor as he diagnoses a patient with low hemoglobin and some odd skin manifestations.  Does he recommend a nephrectomy–and how long does it take to get into such a surgery?  Does the likelihood of a poor outcome prevent the doctor from taking a more aggressive approach, not to recommend any systemic treatment for 43% of those patients? Does he just assume the patient will succumb very quickly to the disease!  Does that create the poorer outcomes in these patients?

A self-fulfilling prophecy is oddly reassuring to the party who makes the prediction, as he unwittingly works to make that prophecy come true.  Poor expectations for survival may well lead to that very outcome.  Wish it were otherwise.





Filed under Guidelines, Newly Diagnosed, Surgery

Younger Patients & Kidney Cancer: Your Genes or Your Luck?

Once you reach a ‘certain’ age, you are horrified, but not surprised to get a cancer diagnosis, or hear about it in a loved one.  That same cancer in a young person is even more horrifying, we instinctively know.

Most kidney cancers (and there are more types than we previously knew) are found in people in their 60s and 70s.  Bad enough, but a cancer called by the same name and found in a younger person is often a very different cancer, with a very different prognosis.

Some new research recognizes that special attention should be paid to those RCCs found in patients 46 years of age and younger.  Why is this?

The quick answer is that this may represent a more aggressive kidney cancer and/or be of a familial or hereditary nature.  That important distinction has researchers strongly recommending that young patients be referred for genetic testing.  This can explain those special risks and create more appropriate treatment plans, and alert other family members as to special monitoring. Critically it may change the approach to any removal of the kidney and/or tumor.

Typically a small renal mass might be monitored or removed by either surgery or some laser ablation.  If removed, the tumor can be assessed by a pathologist–a look under the microscope.Without a prior biopsy, the ablated tumor will not be examined, and no genetic testing can be done.

BIG HOWEVER HERE: even with a good pathology report, that may tell only what that tumor looks like–not what pushed it to grow, i.e., the genetic drivers. And those genes don’t go away with the tumor, so the risk remains that more tumors will grow, maybe in the second kidney, or in the partially removed kidney.  Plus the rest that can happen with cancer…

An 75 year old whose small renal mass is removed will likely function well with one kidney.  That same tumor  in a 35 year old creates another challenge.  If that tumor is driven by familial genes–not just by sheer bad luck–more tumors on the other kidney may be in the works.  A partial nephrectomy   must be considered. The risk of more tumors emerging in that kidney AND the other kidney is high.  The younger patient needs decades of good kidney functioning, but those decades carry the risk of the emergence of more mets.

What else should trigger a genetic testing?

Quick answer: anything that doesn’t look like the senior  citizen with a single tumor in one kidney.  More officially below:

Early onset of kidney cancer is 46 years or less.

Bilateral (two-sided) or Multifocal (many locations) kidney tumors

Family history of kidney cancer, 1 or more close relative, 2 or more in more distant relatives

Kidney cancer with either a mix of other tumor types roughly related to kidney cancer or with lung cysts or pneumothorax (air leaking out of lung into chest cavity)

Personal or family history of kidney cancer syndromes.

The above list is from Yale  School of Medicine, Professor Brian Shuch, who work includes dealing with heredity forms of kidney cancer.

More small renal masses found at an earlier age in more patients, as our imaging techniques improve and more CTs scans are done. Not all will be hereditary, and many will be sporadic or out-of-the-blue kidney cancers.  Those are likely due to the sheer chance. Things go wrong as trillions of cells divide and make DNA mistakes along the way. Years of environmental damage may overwhelm the body’s ability to correct those DNA mistakes–i.e., the immune system gets overwhelmed, tricked, tired, etc.

Kidney cancer found at an early age or with the bilateral/multifocal tumors simply must be tested as to it genetic origins.  This gives information critical to protect the rest of the kidney(s) and to participate in treatment that is more helpful.  Finding an effective treatment will still be a challenge, but proper treatment requires knowing exactly which kidney cancer you have.  From there, a real plan can be developed.

Just as I remind all readers to work with an experienced RCC oncologist–not just a surgeon and/or urologist (sorry guys, we need a team)–those who fall into this early and hereditary renal cell carcinoma category must also work with super specialists.

The person to contact at NIH is genetic counselor Lindsay Middelton at (301) 402-7911. She is with the National Cancer Institute’s Urologic Oncology Branch.  An introductory link is below to the NCI and two other rare kidney cancer organizations.

Birt-Hogg-Dubé syndrome:

Other syndromes causing kidney cancer:




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Filed under Ablation & Radiation, Basics, Genomics & Genes, Making a Plan, Newly Diagnosed, Rarer RCC Cancers, Surgery, Uncategorized

Radiation for RCC? What Really Works?

Is kidney cancer really so resistant to radiation?  Many studies indicate that kidney cancer is far more resistant to radiation therapy than many other cancers. RCC just doesn’t behave as other cancers do, so the most knowledgeable doctors use radiation very carefully.  The typical wider damage that comes with general radiation is not balanced by a good response in RCC.  To be effective, a more specialized radiation is needed.

One of my most knowledge SmartPatients/friend has provided important information about radiation and RCC. The following is a link to  videos, and is followed by advice to a fellow patient trying to understand her options.  SBRT is Stereotactic Body Radiation Therapy, and not at all the same as general radiation, as is explained..

“For right now let me sort of define whats important about SBRT and why it works on RCC. SBRT is all about high daily dose needed for radioresistant cancers.

What is important is the high daily dose for RCC used in SBRT. For example, an SBRT plan for a lung met will use 3 fractions x 15 Gy/day or 5 fractions x 10 Gy/day. Fields will be very conformal to the tumor (but usually not by using shaped fields)

Forget shaped. Conformal small fields–yes.

An IMRT (Intensity-modulated radiation therapy) or shaped conventional plan might use 25 fractions x 10 Gy/day.

And to give daily doses of 15 Gy you need excellent imaging and mechanical capability that not every machine has.

Does it matter? Yes! The recurrence rate for RCC is much higher with low daily doses. The SBRT dose regimes will give about 90% local control (meaning that met never comes back-if you get cancer, it is a new spot.) Standard dose regimes give more like 60% long term local control.

SBRT typically uses dose modulation(which may or may not involve shaping beams ) to control where dose goes.

MLC or block shaped beam IMRT IMRT/IGRT-all use shaped beams but are not SBRT.

Cyberknife and Gammaknife, for example, use no beam shaping-they use hundreds of tiny identical circular pencil beams to build dose covering the tumor.

ANALOGY: Let’s say you have a huge thistle in your lawn. And you have a cup of Roundup. You can go outside 3 days in a row and put 1/3 of a cup on it. Or you can go out every other day for a month and put a spoonful on it. You are more likely to kill it for good with the first method. We want a quick thorough cell kill.”

This SmartPatient does not mince words.  We all want a quick through cell kill, which may bring a met under control permanently.  Not mentioned in this article, is that the body can also have an immune response in the area of the radiation, and deliver a burst of its own cancer-fighting proteins to the area.  This can have an additional effect in countering those super-tiny mets that may be invisible, or just trying to establish themselves in the neighborhood.

Just as there are a range of antibiotics, and we know that the choice of each is dependent up the infection, its location, and the individual’s system, so it is with radiation therapy.  Properly chosen, delivered correctly and to the exact place, with an understanding of the person’s disease, it may be a very effective tool to fight RCC, and not just clear cell.



Filed under Ablation & Radiation, Surgery

Immunotherapy and PD1: Back to the Future of 1992

When I was diagnosed with kidney cancer in 2004, with a tumor that had pushed my kidney toward my belly button, and had filled my lungs with tiny white dots foretelling my death, I had one FDA-approved treatment offered me.  It was that or nothing.  And by nothing, I mean the big, metaphysical NOTHING.  There was no way to nip and tuck away at my lungs to remove the tumors.  It would have been like trying to salvage a sponge by cutting away the black fungus that grew throughout its nooks and crannies.

Systemic disease sounded more hideous than distant metastases. The one treatment–high dose interleukin 2–was already about 12 years old, and nothing better had come along.  The rate of benefit was low, and many hospitals didn’t even bother to offer it.  That is still the case today, with fewer than 90% of kidney cancer patients (and our melanoma counterparts) are told about it.  Desperate patients whose disease could not be chopped out were the candidates, and I was one of them.

This was an immune therapy, described to rev up one’s immune system, just as happens when you catch a cold or have an infection.  It’s pretty obvious that this worked for me, not just to keep be alive while fighting the diseases incursions.  I am free of cancer, though I get a CT scan every six months, a search and destroy-if-we-find-anything mission.  so far so good, and I may even be cured.

PeggyRCCMe, seven –TEN–had to edit it, as I keep living– years after HD IL2 and healthy

No one yet understands why I responded to high dose interleukin, but this old and disrespected therapy has been the silent reminder of the possibility of turning cancer off in the body. New studies are emerging to support this approach.

Just days ago in Chicago, researchers presented information on related immune therapies that offer benefit to some patients,  spotlighting HD IL2 and using immune response to conquer cancer.  Not just to contain or to making cancer chronic, which is laudable in itself, but to conquer it.  Why has it taken so long to use the success of HD IL2 as a beacon to light the way to increased study?

Some say that finding out that HD IL2 worked was plain lucky, but that does not carry the appreciation for the effort that went into it.  Brilliant researchers led the way, but desperate patients of 25 years ago, having no options and fiercely determined to make sense of the devastation of this disease, entered clinical trials, With tremendous risks, no guarantees, and no fall back plans, some died.  Others lived a few more months than expected, which equaled success at that grim time.  Some lived without disease, their cancer conquered and vanquished.  Brave and selfless people, to be admired.

Some new research on the dynamic signaling process that characterizes the growth of cancer has been emerging of late.  Cancer grows by evading the immune system, sneaking under that exquisite alarm and response process, turning off chemical triggers that should remain on to block its growth.  Learning more about that intricate system, a call-and-response process that is just now being understood has brought about agents to support the immune system.

Not just killing cancer cells faster than the health cells are killed–quick version of chemotherapy–these new agents interfere in the cancer growth.  Whether the research will show that response is durable and lasting, as with some HD IL2 patients, is yet to be seen.  But my hope is that this type of research will reinvigorate the interest in using the immune system to return many more patients to health, as was done for me.

PS A new lecture by Dr. Jedd D. Wolchok–blessedly short, though well-explained will be posted shortly.  PD-1 Pathway.  Watch for it.  Also Dr. Sumanta Pal of the City of Hope, my own doctor, discusses ongoing use and sequencing of targeted therapies, both from 2013 June ASCO

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It’s Spread! Is It Too Late to Do Anything?

I love this study, as it really symbolizes the tremendous change that has occurred in kidney cancer treatment these last 6 years. It is remarkable that the 124 patients are described as having already received first- line treatment, and were now in their second-line. These same metastatic patients might have received neither just six years ago.

The study was really not to compare the response to the treatments received, whether Sutent (sunitinib),  Nexavar (sorafanib), or placebo.  (Why any party chose or was chosen to receive a placebo is another, darker question.)  That the median follow-up was 80 months is a triumph by itself.  This is in contrast to the clinical trials that often show just a few months extra time which we and politicians can focus on, when the reality of much longer responses is clearly shown here.  Of course, these longer survival times came from those trials which showed those few months–and this shows the reality of many more months and years of life!

Metastatic tumor burden(TB) was measured, based on the size of the sum of the longest unidimensional diameter of each targeted lesion.  The additional increase of 1 cm (about 3/8”) was significant in predicting response to the medications. Siimply, adding the one-direction measure of the lesions and comparing them showed that more tumor was a bigger problem.

One can also assume that to remove as much tumor as possible may be helpful in maximizing the benefit of the meds given, although this study does not address the actual types and locations of the mets, nor indicate why no other therapies, surgery or ablation, were used.  With 124 patients this would represent a mix of individual experiences, more like the typical patient group.

What does “median follow up of 80 months” really mean?  A median is not an average, but a measure of the time point at which ½ of the population studied had follow up less than 80 months and ½ had follow up for more than 80 months.  Since this is considered a long time in clinical trials and becomes more of a longitudinal study, we may never know the average length of time that these patients had either PFS (Progression Free Survival—time until the mets began to grow again) or OS (Overall Survival).  In any case, we are aware that following this second-line of treatment, there are still more therapies and interventions which may be available.  And even more options are up for FDA approval as I write.

All these options and the greater success of each muddies the study waters, but clarifies the hopes of those with metastatic RCC, or are at risk. This study proves that tumor burden (TB) is a disadvantage. Most patients have naturally assume that more cancer is worse for you than less cancer—who knew? But this gives weight to the notion that the removal of some tumors, if not all, can be beneficial used with targeted therapies. In the past, some oncologists have discouraged additional surgery in the light of metastases, with the implicit message, “It’s too late, and won’t help you anyway.”  Not the doctor for me.

The story is quite different right now, but patients may need to tell this to their doctors–in the language that the doctor speaks. Certainly, there was a time at which doing more surgery for mRCC patients added little, if anything, to survival and probably even less to the quality of life. That no longer is the case, and those older studies no longer have meaning.  While each patient must be treated as an individual, in light of all the variables that impact his health, there is increased optimism for the metastatic patient. Aggressive and early treatment can no doubt extend life and make it worth living.  


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Filed under Ablation & Radiation, About Peggy, Biological Systemic, Clinical Trials, Immune Therapies Old & New, Medications, RCC Basics, Surgery, Targeted Therapies, Your Role

Immunotherapy Part 3: Am I Cured? And How Big is 9mm?

Halfway through my high dose interleukin 2 (Proleukin) treatments, having completed weeks 1 and 2 and into the second rest period, I got the second most important scan of my life.  The most important CT scan changed my life, with its image of a tumor larger than a baseball, and countless tiny specs of white death in my lungs.
This new scan in August of 2004 would let me return to the hospital for more of the immune stimulant, Proleukin, which revved up my internal immune system to the max. My system was then to recognize and fight off the residual kidney cancer that had settled visibly in my lungs and any other new sites, as yet unseen.  The new vocabulary of cancer forces me to say that while hundreds of tiny lung mets/lesions/nodules–no wonder we patients get confused–were not just there, but ” visible”.  Implicit was the message that many hundreds more were  invisible, certainly  alive and thriving, just not yet “imaged”.
The tools of imaging cancer are varied and unequal, some more effective for some cancers, and yet inadequate for others.  First of all, the tumors are measured in centimeters and millimeters, and that language shift alone makes them even more inaccessible to Americans.  Just how big is 9 millimeters anyway?  And a centimeter seems a pretty vague measurement after years of holding thumb and forefinger together to how 1/2 inch with decent precision. Is a change from7mm to 9mm cause for alarm?
Plus the panic of hearing “cancer” drives any math computation out of one’s head.  The only math question that can be asked and then not understood is, “How long have I got, doctor?”.  And then there is the matter of what can be seen with which instrument.  When doctors tell smokers that their  x rays are clear,  naive civilians translate that to mean their lungs are free of cancer. A rough interpretation might be more like, “Your tumors–if you have them–aren’t big enough to be captured by this 100 year old device.  Come back when we can see something/you are pretty much past help.”  Notice that I provide the translation here.
The x ray is more like using a child’s microscope to look at something; great for noticing crud on your pet’s hair, but not quite like those grownup electron microscopes which can see cells.  Note to kidney cancer patients–don’t even bother.
Another imaging device is a PET scan, which measures the activity of cells, and which I understand a quick snap shot of liveliness of the cell, and it manifestation, the tumor.  Is it chowing down on the body’s nutrients faster than the orderly cells?  That activity will “light up” in a PET scan, so the lazier cancer cells might be overlooked.  Not to effective in kidney cancer, whose tumors are often slow-growing.  That is also possibly why kidney cancer can establish itself so thoroughly in so many patients, not noticed until a broken rib or vague back ache or a non-existent ulcer finally results in a CT scan. Note to lots of kidney cancer patients–don’t even bother with a PET scan.
So a CT scan, with contrast to enhance the vague and ghosty images is the way to go for most RCC patients.  A blood test to see if the single kidney can handle the assault of the imaging fluid precedes the test, and then the patient settles onto a big padded tray which is drawn slowly into a large doughnut-shape machine that somehow can see into the patients insides.  I’m not even trying to explain that.
That exam is not painful, not pleasant, and not anything you can study for; you simply submit, as patients are supposed to do, and then the impatience begins.  Most patients must wait to get their results from the doctor, and this is the longest wait of one’s life.  Am I dying more efficiently than before?  Are the cells multiplying more quickly?  How long have I got, doctor?
But I had learned the secret, which I now announce to all.  You are ENTITLED to your own reports, and with a bit of research as to when they get read, you can go get them.  Apparently for many imaging centers, this comes as a surprise, but we are all grownups and can explain that.  Sometimes your doctor will need to hear that too.  I have always just called ahead to the “Medical Records” department and asked for the report to be ready, as I have no patience…again.
But in August 2004, I had to be outside before I could read it.  To read a report of impending death inside a hospital with its metal window frames and linoleum floors and sad, bent people waiting their turns is too harsh a setting.  Immediately stepping outside, I could rip open the envelope, and read that my lung tumors were shrinking, even those big ones.  The 13mm lesion was now 8x9mm, the 8x7mm lesion was just 4x4mm.  And the countless other unmeasured one?  They were likely shrinking, too.  And 9mm is .354 inches, which I still can’t measure between my thumb and forefinger, but the CT scan could, and that was good enough for me.
Back to the hospital, a much easier trip than before, to get two more week-long sessions of HD IL2. The mets were shrinking and I was getting more ammo against them.  The cloak of invisibility was pierced and my immune system was working again.

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Immunotherapy Part 2: Is There Any Hope?

My first week at home following the CT scan was to be a recovery week, following five days in the hospital. When I had anticipated that first weekend, post Proleukin/High Dose InterLeukin 2 treatment, my plan was to go to a local kidney cancer meeting.  I would be a bit soggy, post “flu”, but not contagious, just recovering from the immune stimulant.  I planned to sit around, smile bravely, and look like those heroines in the old days of consumption.

As a measure of my mental competence, it was several weeks later before I realized I had missed the meeting, and in fact, had missed most of the week, and a good portion of the recovery week as well.  My response to the Proleukin was such that I did not receive but 9 of maximum 14 doses and had to spend an extra day in the hospital to recover.  The last thing I do remember of that week at UCLA was a doctor walking me down the hall, and seeing a sign overhead.  At least I could read, and knew I was in the hospital, and then somehow I was home.

Flashes of memory come to me of those first few days, retching in the toilet, and then being sat in the shower on a tiny plastic stool, and being scrubbed by my daughter, a miracle of an experience. And more odd oblivion.  At this time, my mother-in-law was headed deeper into an oblivion of Alzheimer’s, and I joined her.  One WEDNESDAY morning, I was reading the paper  v e r y s l o w l y…not my usual style, and I noted that the LA Times used Tuesday’s date.  Obviously this was major mistake, which rather incensed me, and tried to interest my husband in this crisis.  “What day is it?”  He also thought it was Tuesday!  For that matter so did the local paper, and the Wall Street Journal!

Naturally, I had misread or misheard this, so checked again, and asked again, and asked again, and read again.  Even the damn computer was in on this mistake, but I waited patiently for corrections to occur, and still they–now the entire world–claimed it was Tuesday.  And the family was getting a little odd in their responses to me. “Still Tuesday, Mom…”.

Not once all that Wednesday nor the Wednesday that followed it did I ever think for a second that I might have been mistaken.  My testing, my logic, my checking and rechecking all these reliable resources did not change my mind, but it did cause me to wonder why everyone else was wrong.  I figured the nice thing to do was to wait until they got it right.

It took me several months and a number of similar events to realize that this was a tiny gift from HD IL2–and insight into craziness, or whatever word describes the inability to accept fact in the face of facts from trusted and even beloved sources.  No wonder poor Nana could get so angry at all of us, and no wonder that telling her something in a logical manner was futile.  Her brain had been compromised by Alzheimer’s and mine by the medication that was trying to save the rest of me.

So was it working?  Brain issues aside, I felt fine, or so I told my oddly polite and amused family.  Taking a plate to the sink proved to me that I was doing all my household duties.  Writing a 25 word email in 30 minutes proved my computer skills were intact.  But what about those precious lungs and the icy white granules of tumor dividing relentlessly?

Without proof that the IL2 treatment was slowing down the growth, I would not have been permitted back into UCLA.  To push the immune system into the kind of response that causes it to seek and destroy the cancer cells so well-settled into my lung, not only the visible ones, but their countless and invisible spores, is dangerous.  No doctor wants to make a patient sick without hope that this synthetically induced sickness would drive out the virulent and relentless cancer cells, so it had to be shown to be worth the risk.

As I really became aware that I had missed one week and more in my life due to the treatment, and that I had no control of memory over what had happened in the hospital, I realized how hard it would be to readmit myself to the hospital.  Excuse after excuse–all good ones, of course–delayed my walk into the lobby, accompanied for the first time by fear.

Years earlier, as my father lay dying in our family room, he told me that he was afraid to go to sleep, for feared he would wake up dead.  We grinned wryly, and promised not to let that happen, though it did–everything but the waking up.  I was raising my hand and volunteering to do  just that, walking back in through the gray and damp parking entrance to UCLA.

Coming out the second week with equal blank spaces and some low blood pressure “events”, I was still alive, and could plan for my CT scan.  Back to the same place where they had first found and failed to tell me of the lung mets, and let them try again to “image” them.  (Is image now officially a verb?) One thing remained in my brain, and that was the knowledge of how to get the report from the CT scan done two weeks plus into my rest period after week two.

My son drove me to the scan center, as I was oddly not thought to be capable of going there myself, such a smart family, and parked as I rushed to collect the report.  It was at the desk, as promised, and I tore open the envelope, and pulled up the last few sentences of the report into view.  “Significant decrease in size of multiple pulmonary nodules!”

And back for more Proleukin.  And a cake that I ordered for myself, which read (Charlotte’s Web alert) “Zuckerman’s Famous Peg…Amazing.”



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Filed under About Peggy, Biological Systemic, Immune Therapies Old & New, Surgery

Integration of Surgery (Cytoreductive Surgery) and Systemic Therapy in the Treatment of Kidney Cancer


So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”

PART Two of Several Parts;

“Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone”

Dr. Christopher Wood

Integration of Surgery and Systemic Therapy in the Treatment of Kidney Cancer

Also referred to in the KCA program as “Role of Cytoreductive Surgery in the Treatment of Metastatic RCC

UT MD Anderson Cancer Center

April 14, 2012; KCA National Patient Conference

Cytoreductive Surgery for Metastatic RCC: It’s Not for Everyone

Identifying Patients Who Will Not Benefit from Cytoreductive Nephrectomy

Cytoreductive surgery is not for everyone. Certain patients will not benefit from surgery.  We (MD Anderson) did a study to see if we could accurately select those patients who would not benefit from such a surgery, to save them from a surgery likely to be highly morbid and not beneficial. We compared 566 patients undergoing surgery to a group of 110 patients were treated with their tumors in place and treated with medical therapy only.

We tried to predict for which (patient) factors predicted outcome.  We at MD Anderson can be very aggressive in our surgeries as we believe in cytoreductive surgery, so these patients who could not have surgery were probably the worst of the worst.  For these patients, treated with medical therapy only, the median survival was only 8.5 months.

With that in mind, we looked at those patients who underwent surgery.  If those patients did not live beyond 8.5 months after surgery, they probably did not benefit from that surgery.  What factors predicted for those patients to live longer than the 8.5 months than did the medical therapy alone group?

What factors would be predictive of how one would do? We identified the above factors; low serum albumin, an overall nutritional status lab value, elevated LDH, also a blood test, the presence of liver mets, presence of symptoms due to those metastases, retroperitoneal lymph node involvement, (discussed earlier as a bad sign),supra-diaphragmatic lymph nodes and locally advanced T state.  All of these features predicted for a worse outcome.

If a surgical patient had three or fewer of those features, he did significantly better than those who received medical therapy alone.  But if a surgical patient had more than three of these features, that outcome was the same or worse than those who received medical therapy alone.  So now we are using these features to prospectively select patients for surgery.

Can We Do Better?

Is the relevant question whether or not surgery should be incorporated into the management of metastatic kidney cancer?

I argue the more relevant question is whether there is a role for “pre-surgical therapy” for metastatic kidney cancer.

Pre-surgical therapy means to give some targeted therapy for some defined period of time, then go to surgery and resume targeted therapy after surgery. The potential benefit may be to use the pre-therapy as a selection process: patients who do well are those taken to surgery, and the ones not doing well are spared a surgery that not likely to give them benefit.  It allows us to harvest (surgical) tissue that has been treated with these agents.  With that available, we can study it to see how targeted therapy affects the tumor, what pathways are turned on and off, to help generate the next treatments.  It may shrink the primary tumor and make the surgery easier, most important this is that it allows us to spare patients from surgery that they are not likely to benefit from.

However, targeted therapies don’t just target the tumor. They also target wound healing, which is why many patients who get this therapy have wound complications. The tumor will not respond to the therapy and may grow; a patient who was a surgical candidate all of a sudden becomes not a candidate for surgery, because the tumor has grown. He may need a more extensive surgery. The more I take out, the more difficult it is for you.  And timing is everything. If you get targeted therapy and respond well, why stop that to send you to surgery?  And as a surgeon, if you are not responding to targeted therapy, why would I want to take you to surgery?

Potential benefits are that the primary tumor may shrink, may downstage or downsize, and make surgery easier. Maybe we could do partial nephrectomies on everybody, save some kidneys.  It may make the unresectable become resectable.  It may improve prognosis. In patients without metastatic disease, it may eliminate micro-metastatic disease. (Pre-surgical targeted) therapy might be used as a litmus test of response, but there are risks, including surgical morbidity and lack of response. Plus there is pre-clinical data which suggests that in some cases, targeted therapy, treated in this fashion, may make the biology of the disease worse.

This is the MD Anderson trial with Bevacizumab (Avastin), where patients were treated with Bevacizumab for two courses of treatment and then went on to surgery and back on Bevacizumab after surgery.

We recently completed this Sunitinib trial. Patients completed two courses of Sunitinib, followed by nephrectomy and went on to receive Sunitinib post operatively when they had a response.


This is my Axitinib trial, where patients with locally advanced disease would receive three months of Axitinib, and go on to get a curative nephrectomy

Dr. Kamar showed you earlier an evolution in surgery over time.  Ten years ago, everyone got an open nephrectomy; it was done open and very morbid.  Then people began to use a partial nephrectomy and then a laparoscopic nephrectomy.


Each advance had to prove it was equivalent to the existing technique doing then and each had to show oncologic equipoise, i.e., equivalent cancer control.  To give equivalent cancer control was the most important hurdle for each advance in order to be accepted.  It also had to spare nephrons, for me, that the least important thing was this it was minimally invasive.  Between a minimally invasive operation that doesn’t work, and a maximally invasive operation that does work, which one would you choose?

Similarly this neoadjuvant approach has hurdles. It must be safe and it must have improved outcomes.  The least important is that it downsize or downstage the tumor.  It is the rare patient who presents that you can’t resect.  It would be nice if the tumor shrank, but that is the least important, I think.

Is NeoAdjuvant Therapy Safe?


Is neoadjuvant therapy safe?  This patient (on the left) went on Sunitinib, had surgery and went on to get Sunitinib after surgery.  What I did not know as the surgeon, that the patient started Sunitinib two weeks after surgery. And he had complete abdominal wall dehiscence (opening of the wound).  That is his greater omentum sitting on his abdominal wall.  The patient did not even realize that he had a problem and went to the MRI for his repeat staging study. He had no idea that he had a problem, so went he came to clinic and we saw that we went, “Oh, my God!”

Referencing another slide not shown here: On the right is a patient on the bevacizumab trial who had abdominal wall dehiscence, four months out from surgery.  That is her small bowel (referencing upper portion of CT scan) and you can actually see it on the abdominal wall.

“Is this safe?”  We did a retrospective study on 70 patients using pre-surgical therapy and compared them to 103 patients who had upfront cytoreductive surgery, and we looked at complications over 12 months.

Patients who had pre-surgery treatment did not have more complications than those who had upfront surgery, nor were there more severe complications.  However, they were more likely to have late complications, and to have more than one complication if they had a complication. They were more likely to have wound complications, related to the targeted therapy and wound healing.


Looking at a multi-variate analysis, all the factors that predict for poor wound healing, the only factor that was significant was pre-surgical therapy.


Thus patients who get this therapy before surgery have a higher risk of wound complications—but not a higher risk of overall complications.  They have a higher risk of wound complications, but for overall complications, it is the exact same risk as patients who got upfront surgery.

Patients who had a decline in their serum albumin while they were being treated had greater problems with wound complications. Serum albumin is seen as a marker for nutritional status. Now we follow that variable and find that for patients who have serum albumin decline, we are more likely to reinforce their wounds with surgery.

Happily, patients who received pre-surgical therapy did not have a worse survival than those who had upfront surgery, followed by systemic therapy.  They may not do better, but they do not do worse, and that is an important feature and shown here graphically.

So What About Tumor Downstaging/Downsizing?

In the era of classical immunotherapy with interferon and IL2, with the primary tumor in place, the primary tumor never responded. That in part, was the impetus to take us to cytoreductive tumor, since the primary never responded.

These patients were treated here at MD Anderson.  This is a patient had a very locally advanced tumor, and very large lymph nodes. Had this been done as cytoreductive upfront surgery, it would be a huge operation. Treated with Sunitinib and he had dramatic regression in the primary tumor, the nodes all went away, and he was able to have a laparoscopic nephrectomy. Arguably, he benefited from this approach.

This patient was treated with Axitinib for a very large locally advanced primary tumor here, treated with Axitinib, (on right CT). On the right, there was dramatic regression of the tumor.


Here’s a look at the specimen we removed.  Here is the tumor sitting in the kidney right here, and arguably, this patient could have been treated with a partial nephrectomy.  We wanted to do that, but they were reluctant.

This is another patient treated with Axitinib, that received neoadjuvant therapy, and again you can see (on left) a very large locally advanced tumor sitting in the right kidney.  He received Axitinib and after three months, and you see a dramatic regression (right CT).  With this he would have had to receive an open nephrectomy and with this, this patient can undergo a laporascopic nephrectomy.  Much less morbid.

Here’s a picture of the specimen, dramatic improvement. All of this used to be viable tumor, nowhas been killed by the Axitinib and this rim is the tumor present.

Are These Just Anecdotes, or Can We Rely on These Agents to Downstage Tumors? 

I would argue that if it is true, as a surgeon, I would say, give it to everybody.  Maybe we can offer partial nephrectomies to all our patients.


So what is the data? This study looked at 17 patients treated with their primary tumor in place with Sunitinib.  Only 23% of the patients actually demonstrated had a response, but those that did had a response rate of 31%.

At the Cleveland Clinic, the patients were treated with Sunitinib, and the overwhelming majority had little or no response in their primary tumor.  In some patients, their tumor grew while on treatment.

Data from our Bevacizumab trial shows the recurrent theme; the overwhelming majority of patients had little or no response in their primary tumor to targeted therapy.


The University of North Carolina tested Sorafenib. Again, there were some dramatic regressions, there were some dramatic progressions, but the vast majority of patients had little or no response in their primary tumor.

Trying to determine once and for all, we want to ask whether there should be this treatment with the tumor in place.

In a larger study of 168 patients treated with tumor in place, we looked to see there would be tumor shrinkage.

Reasons for not removing the tumor is below, with the vast majority not considered good candidates for surgery, or were enrolled in a clinical trial.


These were the therapies they received.  The vast majority received Sunitinib, which is the frontline standard of care, with other therapies intermingled.

As to the response rates, we had some patients who had dramatic progression of their tumor, some patients who had dramatic regression of their tumor.  The vast majority of the patients had little or no response in their primary tumor.

One of the things that is common in the community is that patients with large venous tumor thrombi may hear their community oncologist say, “Here, take this medication, it will shrink your thrombus and it will make your surgery easier.” So is this data true?

A significant patients will present to me on Sunitinib.   In this series, 48 patients had different levels of tumor thrombi and were treated with these agents.



Unfortunately, a recurrent theme (references “Stable Disease in 75%), patients had little or no response in their tumor thrombus. In fact, 15% of patients progressed while in treatment.  Only 10% of patients demonstrated shrinkage in their venous thrombus in response to treatment.

Initial Body of Evidence Would Suggest that Significant Primary Tumor Downstaging Will NOT Be Realized with the Current Generation of Targeted Therapy Agents

 I would suggest that the initial body of evidence suggests that significant primary tumor downstaging will not be realized with the current generation of targeted therapy.  Nevertheless I must confess that I have been quite impressed with the responses that we have been seeing with Axitinib.  Every patient has had a response.

As to the report card on presurgical/neoadjuvant therapy.  I would argue that it is indeed safe.  We see more wound complications, but those are pretty easily dealt with. It does not seem to reliably downsize tumors. I would this does not. Is this worth doing?  Should we continue to do this clinical research at MD Anderson and around the world to determine if neoadjuvant therapy has a role in the treatment of patients?  I would argue that it does for the following reasons.

In our Bevacizumab trial, 50 patients were enrolled, but only 42 underwent nephrectomy. Six patients had disease progression and went on to salvage systemic therapy rather than nephrectomy.  These six patients were saved from a surgery that would not benefit them.

In our series, we asked, “Is there something about pre-surgical therapy that we can use to predict prognosis, and can we use the primary tumor as a bio-marker to predict outcome?”


This is a spidergram looking at primary response in the tumor. We noted is that patients, who did respond in their primary tumor, they responded early.  If you don’t see it early, you will not see it; there is no sense to continue treatment if you don’t see some shrinkage.

Those patients who had at least a 10% reduction (in the first 60 days) in their primary tumor size went on to have their tumor shrink almost 25%.  If patients did not have that 10% in the first 60 days, they were likely to have little, if any response.

So we could predict who was going to respond in the primary tumor, so the question was, “Can we use that as some sort of bio-marker?”


We treated 75 patients with Sunitinib with their primary tumor in place, and we found that those patients who had a greater than 10% response in their primary tumor had a significantly greater survival than those patients who did not have that early shrinkage of greater than 10%.  If they had a greater than 10% response within 60 days, their survival was even better.

And that was in univariable analysis, and it also held up in multivariable analysis.




For the first time, looking at the primary tumor’s response to targeted therapy could be used as a prognostic variable for outcome of patients.

In Europe, there was another study, looking at Sunitinib. They arrived independently at the same conclusion that we did, that those patients (treated with their primary tumor in place) with a greater than 10% response in their primary tumor, when treated with their primary in place, had a significantly better outcome than those treated patients who did not.

Cytoreductive Nephrectomy for Metastatic RCC in The Era of Targeted Therapy

Not a question of “IF” but “WHEN”?

I argue that cytoreductive nephrectomy is not a question of “if”, but really more a question of “When?”


This trial that is currently ongoing in Europe through the ERTC, the CERTIME trial. Patients are randomized to cytoreductive nephrectomy followed by Sunitinib versus two course of Sunitinib followed by nephrectomy.  This examines timing of the nephrectomy, not whether we should be doing a nephrectomy.  This is a much more relevant research question, and this trial is accruing quite nicely over there.

In conclusion, targeted therapy has dramatically improved the outcomes for patients with metastatic RCC.  Efficacy in the adjuvant and neoadjuvant setting still is under investigation.  Without complete responses from this targeted therapy, surgery will remain an integral part of a multi-disciplinary approach, both as to control of the primary tumor and as metastasectomy. Show me an agent that demonstrates reliable and complete response, I will be the first to argue that we need to reexamine the paradigm.

Do not think that pre-surgical therapy is the standard of care.  It is not.  It has merit, but it needs further study and validation.  It is not clear to me when it is appropriate to integrate surgery into the context of receiving systemic therapy.  Thank you very much for your attention.


Questions and responses from audience.


Audience. “My question is regard to your last comment, as to the immediate impact of say, Sutent, showing up prior to surgery with an early response, does that also mean that Sutent–having a response in metastatic disease–does that tell you than an early response also means a generally better outcome?

Dr. Wood: I’ve got to tell you we haven’t looked at that, but that is a very worthwhile study to do.  Intuitively, my answer would be yes, but I don’t think that we have anyone who has done a formal study on that. It is a very good question.


Audience: “How should ablation and the small tumors be monitored if you have those small tumors like less than 3 cm, like if you are a tumor producer, if you have “multi-foci” tumors?”

Dr. Kamar: Do you mean after or before the ablation?

Audience: “Before the ablation.”

Dr. Kamar: While you are on active surveillance?

Audience: “Yes, and if you have multiple primary tumors less than 3 cm.”

Dr. Kamar: This is more common in patients who have VHL syndrome, which is a syndrome where patients have a tendency to have more than one tumor in their kidneys.  The follow up is every six months or so, so we don’t really want to image too often for the radiation risks that are involved with doing too many CT scans.  Initially every 3-6 months and after the first year, move to every six months or one year.  It also depends on whether the patient is young and healthy and why would we want to observe.  In VHL patients that is done commonly, because we wait for the tumors to become 3 centimeters before we intervene.  We don’t want to do surgery when the tumors are only 1-2cm in that particular patient population.

Wood; The 3cm we are talking about comes from the NCI where they have a huge experience in treating genetic kidney cancer, and they noted that patients with tumors 3cm or less never metastasize.  So we use that 3cm size as a sort of trigger to tell us when we need to do surgery.  With multi-foci disease, once it hits that 3 cm size, we will go in and debulk the tumors from the kidney, take all the tumors we can take out, and then follow them over time.


Audience: “I have a question re ablation.  Is that an option if you have metastasized to your lungs?”

Dr. Kamar: You mean to use it on the lung tumor?  (Yes) Do you mean on the mets or do you mean on the tumor in the kidney.

Audience: “No, my kidney is gone, but I have metastasized to the lung, and I have had cyberknife, but is it an option to be used on the lungs.”

Dr. Kamar: I think it is an option, but typically, if it is doable by surgery, which is the preferred way.  The ablations that are done outside the kidney are mostly done for bone lesions, where cyroablation of RFA is done, because it is typically harder to remove a lesion from the bone than it is from the lung, for example.  It is more commonly done for liver metastases if anything

Wood:  It is more common to use it to treat symptomatic metastases, but there is some interesting work going on here at MD Anderson by one of our colleagues, where there may be some immunologic phenomena associated with ablation.  We have some case studies that have been done, where patients who have undergone ablation, particularly RFA, not so much Cryo and had a complete regression of their metastatic disease, almost like a vaccine had been put on the met, and actually Seren is studying that with alone and with some of the immunologic agents that you will hear about from Dr. McDermott to see if that may be a viable treatment option for patients with kidney cancer in the future.


Audience: “After ablation, do you usually see necrosis in the body of the tumor? Can you see that during imaging?”

Kamar: You can see that afterwards, and typically more common with cyro. You see necrosis, coagulative necrosis.  Typically it is coagulative to the tumor. You see that on the pathology, when you end up removing that tumor later on. So what we see is absence of contrast enhancement. The tumor before treatment was lighting up when you give contrast. After the procedure, it stays dark. That is our best indicator, other than biopsy, that the tumor is really treated by radio frequency.  We don’t see really necrosis on imaging quite like for larger tumors like Dr. Woods showed earlier.

Audience: “So during subsequent imaging, you might see necrosis?”

Kamar: You might but typically what we look for is absence of enhancement.  Necrosis is not something we reliably see or depend upon for follow up.


Audience: “For Dr. Wood, re venous thrombosis, do you insert an IVC filter prior to surgery, I’ve heard, or do you consult with cardiology to get that done.  Is that helpful?”

Wood: Definitely that is not helpful before surgery.  We have both had patients where some guy on the outside decided it would be helpful to put a filter in the vena cava, just in case a piece of the tumor thrombi broke off.  It made surgery extremely, much more difficult.  After the thrombus has been removed, in some patients we will leave a vena cava filter, which is like a screen put in the vena cave, so that blood clots below that screen blocks them from going to the lungs.  A large pulmonary embolism could be fatal.  So patients who do have evidence of a clot down in their legs, we will put a filter in, but if they don’t have any evidence of that, typically we don’t.






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Integration of Surgery and Systemic Therapy/Cytoreductive Surgery in Treatment of mRCC

Dr. Christopher Wood

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

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Immunotherapy for Metastatic Renal Cell Carcinoma; David McDermott, M.D.

 Status of Immunotherapy in Metastatic RCC in 2012

(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.

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.


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%
            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.


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.”

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