Category Archives: RCC Basics

My Tumor MicroEnvironment! What Me, Worry?

It’s bad enough to worry about having had a tumor, but now we are learning that the microenvironment of our own systems–and their microlocations–are important!  What is next?  And what is a tumor microenvironment anyway?

My own primary tumor apparently was quite efficient in spinning off its alien babies, the metastases which peppered my lungs.  None of these ambitious invaders seemed to have found a happy home in my bones, so one could think that my lungs were a nicer neighborhood or microenvironment for my mets.  It is bad enough to have the cancer on the move.  Does this mean that mets in one place will predict mets in another?

To answer this question, it is helpful to understand how cancer cells move through the body and find their new unhappy-making homes.  Happily  for us, as the hosts of these unwanted and busy guests, the body does try hard to limit their invasive moves.  And the presence of our healthy cells and the general brakes of our immune system do offer some protection.  Editorial note here; It wouldn’t hurt one bit if you do everything you can to support your immune system, and make it efficient in keeping you healthy.

For cancers to grow beyond their original location, individual cancer cells have to escape the primary tumor.  Think of tiny ships leaving earth’s atmosphere, pulling away from the tethers of gravity and the support mechanism inherent in the tumor environment. Then those cells must survive the ride through the blood or lymph system, which is really designed to break up the cells, before landing at a new and unknown site.  Cleverly, there may have sent out certain proteins in advance to, to fertilize the ground of that new colony, but the seekers may never find that soft landing.  And then those same cells need to support themselves, far from home.

Researchers tell us that tens of thousands of cancer cells can be shed into circulation every day, but less than 1/100 of one percent of them ever survive to relocate and reproduce.  Lot of good things happen to stop that.  And those darn cancer cells use platelets as shields against the vigilant immune system and recruit clotting mechanisms to strengthen their structures. Some might even take on characteristics of stem cells as camouflage.

Should that tiny colony of cells find fertile ground, they must survive many challenges before they can grow and cause any real impact on our systems.  Researchers and patients are aware that certain cancers seem to have favorite metastatic sites, with lungs and bones the preferred new locations in kidney cancer.  Just to make things more confusing, there are several ways that cancers grow, which seems to depend on the original source of the cancer.  And there are local growth factors, quite normal and appropriate in the bones, which can be subverted into helping establish new metastases.  It’s as if the cells looked around and found local cells ready to collaborate with the enemy!

But that same collaboration and the resources that this unholy partnership brings the new relationship gives an opportunity to prevent the invaders from settling in comfortably.  Noticing the chemical welcome mats, researchers are aware of the possibility of “pulling that rug out from under” the newcomers, and making them less likely to set up shop in your bones or lungs.

They have been especially helpful in preventing bone metastases by using some agents that were developed not as anti-cancer agents, but  to strengthen bones in general.  Since breast cancer also moves to the bones, the use of these agents, bisphosphonates and others, is wide prescribed not only in the presence of mets in the bones, but to prevent them. Prevention of mets is an adjuvant therapy–another of those new words for your vocab test.  Examples of these agents are Zometa and Xgeva, each with special characteristics.

In advanced RCC, where Sutent is being used, there are studies which show longer benefit, when Zometa is also given the patient.  Zometa obviously makes it less comfortable for the mets, which may be tiny and unseen, or newly visible on a bone scan, less likely to continue to grow.  And I am for anything that makes is hard for mets to grow, even if they are really still in the neighborhood.

Just as there are many factors which aid and abet the nasty mets to leave home and travel, and take on new disguises to evade the immune system, there are likely many more approaches to limit the welcome at the new desired location.  One challenge is finding those, as is obvious, and more urgent is to understand when one’s targeted therapy is helping against metastases in one part of the body, only to have a new location be invaded by mets.

If you are getting benefit from one targeted agent, but new mets pop up elsewhere, do you stop the Sutent, and risk more mets in the original area?  Do the new mets need a biopsy to see if there has been a change in molecular characterization which may direct the use of the next medication?  Can you add another agent without undue side effects?  None of these questions have clear answers, but a willingness to examine what it happening and how and where any mets might be made less comfortable in their growth patterns is critical.  Wish it were simple, but it is not.

 

 

 

 

 

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

http://www.urotoday.com/Renal-Cancer/tumour-burden-is-an-independent-prognostic-factor-in-metastatic-renal-cell-carcinoma-abstract.html

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

Drug Interactions; Don’t Be Surprised!

At a City of Hope Medical Center, teaching hospital/research center, a pharmacist spoke to our patient group about drug interaction.  She reminded us that we are responsible to follow the dosages, to alert our doctors to ALL the medications we take–prescribed and over the counter, herbals and supplements. “Remember that diet and its fat content affect our drug’s efficacy”, she added.

 Pharmacists consider three types of interactions, which can happen between drug and another, with drugs and food or beverages, and drugs and conditions under which a drug is taken.  They are described as follows:

 1)     Pharmokinectic issues of absorption, distribution, metabolic and excretion—how does the body bring it in, how long is it in the system, and where does it get absorbed?  Does one drug slow down the effect, or prevent its use?

2)     Pharmocodynamic effects occur when drugs with similar properties to one another are used together.  They may interact with one another; such interactions might cause one or more to be ineffective, or too effective, or with side effects that are unexpected.

3)     Toxicity may happen if the combinations of drugs have a toxic effect on an organ that would not occur with just one of the drugs. 

For example, soranfenib (Nexavar) should be taken without food, while Sutent is recommended to be taken with food—but never with grapefruit juice. 

 Some drugs cannot be taken with NSAIDS; some are platelet inhibitors, for example.  Sutent’s efficacy may be impaired by taking St. John’s wort, or when taken with barbiturates.

 How do you keep track of all of this?  Speak with the pharmacist whenever you have a change in medication—or right now, since you probably have not done that! Make an appointment to have the time cover all the questions. Bring in ALL the medications you use, even those you feel are “probably” safe or those you are embarrassed to admit you take!  Pharmacists have access to extensive data bases, not only of the prescribed drugs, but also many of the supplements and herbals on the market.

 As to herbals and supplements, she reminded the group that there are no controls as to the quality and quantity of active ingredients in the non-FDA approved supplements, and they can vary dramatically. Meningitis caused by a fungus in steroids produced by a US-company has caused the death of 44 and sickened at least 600 just last year.   

It was fascinating to hear that, “Pharmacists don’t take medications”, but she emphasized that she rarely uses anything. It’s harder to convince her mother! Anticipating problems in the future with family-related conditions, she eats properly and exercises, for example. 

Trust your gut about your body’s reactions.  If something seems amiss, talk to your pharmacist or doctor to be sure you are not having a drug interaction.

Read the labels and follow the instructions.  Not sure when and how much to take? Go back to the pharmacist or doctor for clear instructions.

 Bring a “brown bag” of meds and such to your pharmacist to get a review of your meds. You know you should have already done this, so get going!

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A Second Opinion: How the Heck Do I Do That? And What If?

Second opinion? How do I  dare ask my doctor?  He seems so nice, he helped my mother, what makes me think he is wrong, what if he gets mad at me, how will it affect my care, what if the other doctor says the same?  All this goes through your head when you question the diagnosis or treatment plan you have just been given.  But the failure to ask for that second opinion will always haunt you, and may cost you a better treatment, or your life.

Nothing is more frightening than a cancer diagnosis–except perhaps the fear that you do not have the best advice or the best doctor. At minimum we want options and some control. You mayonder if your doctor really knows what he is talking about–you certainly have no way to judge, except to judge how he handles your request for a second opinion.

If the doctor proclaims that only he is qualified to treat you, and that no one else could possibly offer you anything else, the decision is easy.  Just stand up and walk out, getting all your records as you exit.  Your records are yours legally, of course, and should be in hand even when you work wonderfully with your doctor.

You may value your doctor’s advice, but know that your disease is rare and difficult, and that new information may have relevance to your case.  Can your doctor possibly have all the latest information at his finger tips?  And what about that article which you read on the internet or that your friend sent you from his hospital?

First of all, your doctor cannot possibly be up-to-date on all aspects of care and research into your disease.  One doctor estimated that if read two medical journal articles per evening, by the end of the year, he would be only 400 years behind!  And that was several years ago.

One patient friend through ACOR and its kidney cancer list serv has shared his approach, which has been effective and let him work closely with his doctor, while pursuing questions and potential treatments not readily available through his doctor in Australia.  I have made tiny changes to his letter, as it follows.  Good advice and the results, all relevant to us.

Tony starts: ” I’ll  outline how I start “delicate” discussions and get involvement from the likes of the hospital pharmacist. After working out exactly the treatment I want, I kick-start with a simple email, usually to my (general) oncologist. Importantly, I always attach one only medical study –  which is either current or past year.

My request for a treatment is always based on the conclusion in my cited study. I never offer my own opinion or view. I always keep the email short, logical and free of any argumentative material. This leaves the oncologist in the position of having to either (1) meet my request or (2) find grounds to reject the study itself or (3) to call in experts from other disciplines.

  I  learned that the medical decision making process mirrors life outside the medical profession where business managers and bureaucrats want that proverbial piece of paper in case something goes wrong – in this case it’s the well selected medical study (but finding exactly the right study can sometimes involve a lot of work). I find that
these general non-RCC specialists do respect precise RCC studies as they have no hope of keeping up with everything in every cancer type. Simple logic on basis of a reasonably current medical study is the art.

My simultaneous important method is little known fine print I found in our Oz hospital system where every patient is entitled to a second opinion from every relevant discipline. (Tony is in Australia.)

So where, an issue is complex, I respectfully ask for my med-onc’s opinion on whether we should get a second opinion. That gets a much wider team involved where the med-onc doesn’t want sole responsibility for decision making. All just normal human stuff where it’s not smart to make a decision contrary to a current medical study.

So far, I have pulled off four little feats:

The first was getting the urology department to reverse their initial decision to not neph me (they wanted to try to “reduce” my 10cm tumour with systemic drugs and otherwise reckoned I was at risk of karking it on the table).

Then, I got a thoracic surgeon involved with agreement for a rib resection that would have made me disease free (but surgery was called off the day before the scheduled date for sudden emergence of liver and lung mets).

Then, I got the hospital itself to pay for a shot of the very important zoledronic acid (Zometa) – Unbelievably, it is not on our PBS for RCC unless the patient has high blood Ca. Discussion continues on whether they will pay for the shot.
More recently, after one week into first Sutent round, I discovered from doing my own due diligence that another drug I must take for an unrelated condition dilutes the efficacy of the Sutent by about 50% which is unacceptable. My now well practised email / study / second opinion request procedure got the ball rolling resulting in an embarrassment of riches in a big team my med-onc pulled together.

Next week, for the first time I meet with a further member of my expanded team – an oncology radiation expert.”

 

Tony is obviously engaged in his own treatment, comfortable and motivated to read through medical articles, and choosing those which have impact on his treatment options.  He has done his homework  carefully and backs up the request with the medical article, i.e., in the physician’s language.  Tony puts himself in the equation, by asking if “we” should get a second opinion from an expert, partnering with his doctor in this request.  He has wisely calculated the needs of the doctor, and the system requirements. His results speak for themselves, and can have impact for the next patient the doctor sees!

You may think that this is a laborious process, and one which should not be necessary, but the reality is that it is both necessary and effective.  Getting the best possible treatment and making sure that your doctor supports you in this quest may save your life.

As a friend said, doing these kinds of things may save you someday from waking up dead…

 

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Remove the Beast, but What About Its Alien Babies?

When you have a tumor inside, which has hidden and grown and chewed away at your health for years, no sensible emotions are left in place, and no sense of patience is possible.  All the  advice to wait and see if it is really malignant, get a second opinion from a more experience doctor, just  can’t wish/pray/eat/not eat it into oblivion, go to a really pretty spa in Mexico where they do wondrous things without a knife–they all sound alike.

I’ve always been healthy.  Maybe I really am healthy and can live with this.  Maybe the reason that I have been panting going up stairs, and having night sweats really mean more than menopause.  Maybe they got the report wrong, but why did the ultrasound technician sudddenly go silent and begin to frown.

But reality does intrude, and at Mayo it was a reassuring reality, one which recognized that I was sick, that I needed TLC along with clinical expertise, needed to hear music from a beautiful piano, look at art and flowers, and needed Kleenexes on every table in every waiting room.

Coming in on an overnight flight, with a doctor friend having helped make the first appointment, I was anguished to realize that that I was in danger, and dependent upon people I did not know, and a system that was new to me.  But the moment I picked up the phone at the Rochester Airport, I was connected to Mayo.  Instantly the voice on the other end tracked my name, asked how I was, inquired if I had anything to eat or drink–so that she could schedule me for tests to be run on an empty stomach, and still find me time for lunch.  When was the last time your medical system worried about you so tenderly?

I was brought directly to the intake area, where another person found all my records and my medical itinerary, with numerous pages of tests to be completed that day before my doctor’s appointment.  With a pink marker, she circled the goals, including getting me fed, and with clear instructions, sent me to the first test.  The atmosphere is serene but focused, with people from around the world, all ages and shapes, all coming to Mayo for help they could not get at home, or because Mayo had become home.

My prejudice, having been raised in North Dakota, is that the Midwest teaches people to value kindness and competence, all in abundance at Mayo.  Although the nurse in the CT clinic had seen hundreds of patients in the weeks prior, and perhaps thousands over the years, her pats on the shoulder and gentle questions about my feelings comforted me.  When she told me that she would include me in her prayers that evening, I knew she was sincere, and I was grateful.

My five o’clock appointment, now accompanied by my husband and sister, was both dreadful and calming.  He reviewed the CTs we had brought from California, had all (!) the tests from earlier that day, and did a physical exam.  When he pressed on my belly over the tumor, he could not help but ask, “Didn’t this guy feel this thing?”.  The flash of anger was real, and the set of his mouth made me understand that this was obvious to anyone doing an exam.  My several endoscopies and colonoscopies never included the checking my belly, the simple laying on of hands.

“This will have to come out, along with the kidney.”  So much for the fancy “snip and bag it” approach which seemed so simple.  By now I just wanted it out, without regard to scars and technique, and I had a second kidney. “This has to come out, and I can’t do it until Monday.”  It was late Tuesday, but he understood the urgency in my gut.  My kind of guy.

“Did your doctor tell you that you have mets in your lungs?”  No, I had not been told. The stunning announcement of my life.  I was not  going to be able to get rid of the tumor and go on about my business!  The mets in the lower lobes of the lungs were clearly visible in the CT scan from California.  Were there 15-20 tiny snowflakes of tumor there?  The new CT scan of the day showed a blizzard throughout my lungs.  No way to operate on hundreds of mets, and life changed again.

“And we have to talk about followup.  I will recommend high dose interleukin 2, which can be done here or at UCLA.”  That was the lifeline which kept me being able to listen.To go from the  need of an fairly non-invasive operation, to one which would open my gut and remove a kidney by slices of steel in my belly and then to a situation in which physical removal is possible!  No wonder that people call having cancer a journey with no map.

There is only a goal, which is so simple.  To get well.  To not die too soon.  To not die before my son graduates from high school, to not die before my daughter graduates from college, to not die and leave my children in the kind of pain which I had when my own mother died.  We had a plan, with a drug I had never heard of, and one which had to work.  I had no other option but to live.

 

 

 

 

 

 

 

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Systemic Targeted Therapy for metastatic RCC in 2012

Dr. Eric Jonasch of MD Anderson Cancer Center gave the following talk at a KCA patient conference in April 2012.  “Systemic Targeted Therapies” include a group of drugs, all approved by the FDA in .  the last six years.  These drugs mark a critical breakthrough in providing more options for kidney cancer patients, and their use and complete integration into treatment is still ongoing.

(Where good slides were available, they were used; those which were hard to read have been recreated.)

I am going to talk as systemic targeted therapy for Metastatic Renal Cell Cancer, how we are using it, and the science about it, and how that leads us to new ideas, moving forward.  When we talk about kidney cancer, we cannot talk about just one disease type.  What I am going to talk about mainly is clear cell, and Dr. Tannir, my friend and colleague, is going to talk about the non-clear cell subtypes.

So what is ccRCC?  It is essentially a cancer that looks like this under a microscope, and it was called this, back in the day.  We more recently found that it has a mutation in the VHL gene (Von Hippel Lindau) in the vast majority of individuals with and I also run a clinic where I try to marry the information we have about hereditary kidney cancer with non-hereditary kidney cancer to improved therapies.

This is not to scale; it is 213 amino acids long and for the scientists in the audience, that is mercifully short, and it also has three exons in or three parts, or easier to study than most, but obviously still hard to study.

It essentially regulates how the cell reacts to oxygen.  Obviously, oxygen is our life’s blood, we need oxygen, we need water, we need glucose.  And our cells, if they feel like they need oxygen, they basically sit back and VHL will then take the transcription factor, which tells the cell which protein to generate, and then it breaks it down.  If you have low oxygen state, then the cell will say, “Help, I need oxygen” and the VHL will step back,  the transcription factors, HIF alpha and HIF beta are going to come together and you will get production of proteins, like VEGF which is a growth factor for blood vessels and some other things.  If you have a mutation or something how an inactivation of the VHL gene, you have essentially an ongoing process of these cells, now cancerous, saying—somewhat untruthfully—we need more oxygen, we need more blood, build me an infrastructure.

That infrastructure is as follows:  When we think of cancer we can’t think of cancer cells. The cancer cells are in black on slide and in blue are the stromal cells–the “glue” cells, and above those the endothelial cells or blood vessel cells.  This triumvirate plus other cells generate an organ—and it really is an organ—that we call cancer.  And when we use therapies, we are blocking specific areas there.

I’ll tell you a bit about the therapies we use now and that some of you are on, and what they are actually blocking.

Here is some terminology you are about to hear, some jargon, as we talk about trials.

Progression free survival (PFS)—time it takes for cancer to start growing again

Overall Survival (OS)—time it takes from start of treatment to passing of patients

So the “blood vessel starving” are the antiangiogentic therapies we currently have are listed here, and I am going to go through each of these in details.

Antiagiogentic Agents FDA Approved

1. Sunitinib  (Sutent)

2. Pazopanib (Votrient)

3.  Bevacizumab- IFN (Avastin + Interferon)

4.  Sorafenib (Nexavar)

5.  Axitinib (Inlyta)

mTOR Inhibitors   Mammalian Target of Rapamyin Inhibitors

6.  Temsirolimus (Torisel)

7.  Everolimus (Afinitor)

We also have some up and coming drugs.  And the way these drugs work with graphic shown again—is they block the blood vessels. They try to kill the blood vessels that feed the cancer.  They don’t seem to have much effect on the cancer itself.  That is why you have encountered resistance. That we can shrink this down, this cancer, but we can’t make it go away.  And what we need, and on our wish list, are kidney cancer cell-killing therapies for the future.

mTOR Inhibitors

The mTOR inhibitors, of which there are two, Torisel and Afinitor ( Temsirolimus and Everolimus).  What they do; they are actually working inside the cell perhaps both in the cancer cell and the  blood vessel cell.  And they are blocking particular proteins that seem to be up regulated, overexcited, that give them a selective growth advantage.

There we have on the bottom, kind of a brown color, mTOR, which if up regulated, results in production of and more survival advantage… for the cancer cells—which is shouldn’t have.  What Torisel and Afinitor is block that signal.

So let’s talk about the drugs that in 2012 were currently using.  The one that is probably most commonly used is Sutent or Sunitinib.  It this is a pill and what is does the block those blood vessel cells.  It doesn’t seem to block the cancer cells that much.  It’s given officially 4 weeks on, 2 weeks off, although I don’t remember the last time I prescribed that way for anyone.  I tend to start 2 weeks on, 1 week off as I find people tolerate it better that way, and its FDA-approved now since January of 2006, amazingly, a long time ago.  But it is pretty amazing that we have some people who are still on it, starting in January of 2006. 

The reason this drug was approved, it was compared to the old standard of Interferon. What we found saw was a prolongation of Progression Free survival, the time it took for the cancer to progress.  And this was doubled to 11 months from five months, with Interferon, which some of you might remember as shot you give under the skin, three times a week.  And the top line is where the individual were progressing, where they were on Sutent, and the lower line is where people were progressing on Interferon.

This is what is now call the Overall Survival curves, so essentially what we have here on the bottom is TIME, and the top lines the individuals that are still alive, and what we see on the top line are those on Sutent, and the lower line those on Interferon.  It may not look like a huge gap, but what has happened on these research studies, when we do them, is what we call “cross-over”.  When you progress on one of the drugs, you get to another and another and another.  And the good news about this, it that it raises up the survival expectations to some degree, but it makes it hard to say, “That one drug is the one that is really making the difference.”  Until we actually get therapies that consistently and reliably cure kidney cancer, we will still  have this dilemma of having incremental benefits, but, “Hey, we’ll take them!”

Another drug which has come out and has been used since 2009 is Pazopanib or Votrient.  It’s an oral drug, given daily, once a day.  Same sort of thing, a blood vessel blocking agent.

This was tested in a slightly interesting as you have study where you had no therapy before, or you had immune therapy, and they were randomized, randomly allocated between the Votrient (Pazopanib) or placebo.  I have to say that most of the people were enrolled in non-US sites because it is a little bit of a hard-sell for people, if you have not had any therapy before to be told we’re going to put you on placebo, maybe.

Nevertheless, the trial was accrued to and it demonstrated a very significant progression free survival, the time to progression of the disease for the individuals on the Votrient compared to those on the placebo.  And what we see on the left hand side here, we see one of these showing the charts, with the orange line on top is the group (with Votrient, )people who remained free of progression over time, and the lower line, the people on placebo. And the progression free survival data for the people who had not been on prior therapy was as good as we had seen with Sutent.

We had a trial that is currently completed and is being analyzed to see if Sutent is better than Votrient, and we still don’t know which is “better”, but Votrient is certainly gaining traction because of the fact that it looks kind of promising.

Now its interesting when they did Overall Survival analysis, they did not succeed in showing a big difference, because as lot of people had gotten onto Votrient when they were on placebo at the beginning, and they got onto all sorts of other drugs.

So the next drug we are going to talk about is a little different (Avastin).  What Avastin is –it’s an injectible antibody against the thing the cancer produces, the VEGF circulating in the circulation.  It tries to take it out of circulation, so the blood vessel cells can’t see  it.  It’s given every two weeks, by injection, and officially given with interferon three times a week, so a little less attractive for some people.

This is a bit messy to read; the progression free survival in combination with interferon is substantially better than interferon alone, and this was done to two different studies and the data were true in both these big studies.

Thus we’re pretty confident, that along with Sutent, and Votrient, this prolongs progression free survival.

In terms of overall survival, 21 month for the interferon group, and next to it the interferon and Bevacizumab, 23 months.  Again, in the same ball park as we were seeing with Votrient and Sutent, and not a statistically different figure.  That statisticians take these numbers and crunch them and take p values and such, but still there was a lot of cross over data, and clearly, we are moving up the bar here.

One of my favorite data pieces is from the Sutent study. The patients on that Sutent study who had received Sutent or interferon were treated in countries where there was no opportunity for second line therapies or 3rd.  All they got was Sutent or interferon.  And the people who were on the sutent arm only, and nothing else, had a 28 month survival, and the people who received interferon only, had a 14 month survival.  So that’s an untarnished bit of data, showing the magnitude of benefit that they were receiving.  That is more reflective of what we are seeing in our clinics today.

I wont’ go into this in detail, but bottom line is that. There’s a lot of number and you are probably getting numbered out.  Bottom line we look at historical data compared to these people who are on these drugs and then get subsequent drugs, and we are seeing survival in the two to three to four years.Also known as Nexavar

The next drug we are going to discuss is Nexavar, which was approved in 2005, the first of these drugs to be approved.  Same deal, the blood vessel starving drug, given twice a day, orally.

It was given initially to people who had not been given any targeted therapies before, but had progressed on immunotherapy  and it demonstrated that there was an improvement in progression free survival again. 

If you looked at Overall Survival there was improvement if you took out those people who crossed over.  So again, modest improvements and definitely doing something for patients.

Now when this drug was compared directly to the untreated patient group to interferon, what was happening, was that it did not look like it was better than interferon alone. I just finished telling you that Sutent, Avastin, Votrient all beat interferon, and here we have a drug, that seemingly, didn’t.  Subsequent studies were done which shows that PFS is somewhat better than this trial, but in reality in 2012, this drug is not much used in front-line therapy, for better or worse.  It’s not that commonly used, and personally don’t use it much, based on these data.

What I have been talking about now, has been about individuals who have clear cell RCC, good risk features, and these are features looking at “are you anemic?, is your calcium elevated?, are you feeling and so on.”  These are risk features to decide if a patient is in a good or intermediate risk category versus a not so good category.

 

And Torisel, an mTor inhibitor, which I talked about before, and was tested in this poorer risk population of patients, and was approved in 2007.  Essentially, they took patients who had not had any prior therapies, and they checked off boxes. Do you have a low performance status?, your “good feelingness”, have you had your kidney removed before or not?, have you had anemia?, have you had high calcium?, have you had high LDH?, six categories in all.  If you had at least three of those negative categories, they said, “OK, we’re going to put you on Torisel, and compare you with interferon and with Torisel and interferon in combinations.” And because they know this group of individuals tends to have a lower overall survival, they did an overall survival study.

 

It is a bit difficult to see in the background, but bottom line, that this was the first drug that showed in poor risk patients, that it improved overall survival, compared to interferon.  Does that mean Torisel is good for people who  have good risk features? Those who don’t have overall poor risk factors?  Unfortunately, we don’t have an answer to that since that study has not been done.  But this drug was approved, and we know that Torisel seems to provide benefit for patients with the poorest features.

SLIDE MAY BE MISSING

Does that mean that Torisel shouldn’t be used in a second line treatment where people have clear cell?  No, it doesn’t.  It simply means that those are the data that we have, and in the second, and third and fourth line setting—except for the data I am now going to present—we just have to figure out. “You’ve been on this, we’ve tried that, now let’s try this.”  There’s a certain amount of art to it, as well as science.Also known as Afinitor

Afinitor was approved in 2009 for individual who had received either sutent, sorafenbit or both.  This was a study that asked, “Have you progressed on Sutent or Nexavar?”

If yes, you were entered into the trial, randomized,ie the computer flipped a coin so that you went into the Afinitor or placebo, and we asked, “What was the progression free survival?”

This was clearly better in terms of progression free survival. And that’s why the drug was approved, and it is one of the most commonly used drugs in the second or third line for patients with metastatic kidney cancer.

The new kid on the block is Axitinib or Inlyta, in the second line setting.  Dr. Brian Rini presented these data last year, looking at this, another blood-vessel starving drug.  It’s the next generation, it’s more highly engineered to block more of the VEGF pathways, and it does less of the other stuff, which in some ways might be better, but you might want to have some “playing the field” in terms of stopping things in comparison of blocking one thing.  So what did this data show?

This is the study.  People had previously received one of these prior drugs, Sunitinib, Bevacizumab, interferon, Temsirolimus or Cytokine, and then they looked at the progression free survival.

The progression free survival was longer in the Inlyta(Axitinib) group compared to the Nexavar (Sorafenib), about 6.7 months versus 4.7 months. 

What was interesting, was this was a group of individual who had receive either these targeted drugs before or immune therapy, and it shows it nicely in table form, but what it shows is that if you had received prior immune therapy, the Axitinib or Inlyta was way better than the Nexavar.  If you had received prior targeted therapy, in the same class as Inlyta, then the differences were not that great.  Then it’s better, the Nexavar is better in people previously treated with Sutent, for example, but its not incredibly better, but it’s a clean drug, and it’s very welcome addition to the drugs we have available.  So we are using it and getting good results.

Up and comers.  For the last few minutes we will show Tivozanib, another one of these blood vessel starving drugs.  So we have 1,2,3,4,5, and now six of the same class, and like other classes of drugs, it is always good to have gradual improvement.  It is in a pill form, same sort of thing, blocking VEGF pathways.  There were some combinations, a phase III trial, showing that it does actually do better than Nexavar it was compared to, and is coming down the pipeline, probably an approved drug in the next year.

It is interesting that with all of these drugs, that the newer the drug, the lower the side effect profile as they are getting better and better at engineering these drugs, so at least we are getting a better drug in this class arena.  But it is not dramatically better, and we need something better.

Combinations and Sequences

 So what about combinations?  In oncology, we like to do this, combine drugs.  If you have drug A and that works and you have drug B and that works, then let’s combine it and hope we get a duplicative effect, and additive effect.  Hasn’t really happened unfortunately.

Bottom line.  Combinations at that time have not really consistently been shown to be superior to single agents. You get more side effects and you don’t get more bang for the buck in terms of survival or progression.  Sequencing is really what we do, meaning you start with drug A and move to drug B, you move on to drug C.  That’s what we do in the clinic.  One of the trials that Dr. Tannir has championed is the START trial and we have 80-90 patients on this.

We re looking at, if you start with Nexavar or Votrient or Avastin,  and you get randomized to one of the remaining drugs, does that provide you better benefit?

And there are other trials ongoing like that, the SWITCH trial, for example, going on in Europe, starting with Nexavar, then going to Sutent, or starting with Sutent and going on to Nexavar.

Or the RECORD 3 trial, with Afinitor followed by Sutent, or Sutent followed by Afinitor. We’re trying to figure out whether that works better for some patients than others.

This is a big table put up my former mentor Dr. Michael Atkins, a form thereof in 2006, and its been a gradually refined over the years.  Bottom line is we have favorite drugs for untreated patients in the first line setting.  We talked about immunotherapy before lunch, with Dr. McDermott talked about interleukin 2 and others, we have our blood vessel-starving drugs for that category as well.  People with poor risk features, we have Torisel.

In the second line setting we now have good data from these trials that show that Afinitor and Axitinib probably provide benefit after failing these other drugs, and we have ongoing studies to try to determine whether or not one sequence is better than another. All this is nice, and we’re making real strides, but what do we really need to do?

Coming back to the picture of the cancer, we are good at hitting the red part, (the blood vessel structure), but why, when they get used, are we getting resistance after 10-12 months or so.  Why can’t we kill the cancer cells?

We need new drugs that can block other receptors in those blood vessels cells.  We need agents that can actually fix, look under the hood of the cancer cell, see what is misbehaving there, fiddle with it, and make it act more like a normal cell.  If we can’t do that, kill the cancer cell.  Agents that can actually block novel targets in the blood vessels, so we are looking at new receptors on there, and seeing if those drugs, in combinations with other drugs, can starve the blood vessels, are useful.

I am part of a nano-medicine grant, where the hypothesis is that, the big idea, is that a lot of the VHL proteins are mutated, are kind of wounded, but not dead.  If we can revive them, maybe they can make the cancer cell behave more normally.  One of the ways to do that, to raise the level of VHL, is with a drug called Carfilzomib to validate that.

MET Inhibitors

The last thing is those agents that can actually kill the cancer.  This is amazingly, in 2012, still in the experimental stages. We have a colleague in Stanford, Imato Jatia(?) who has done some of these screens, some people at Harvard, all around the country, and we as well, looking at this strategy, where the cell kills itself.  We have go to perhaps stop focusing as much as getting as yet another blood vessel-starving pill.  An example of one of these drugs that might do this, is a MET inhibitor.  So, a MET is another protein that is found on the surface of the Cancer cell.  There were some reports at ASCO that this might a promising avenue.

So in summary, we are getting really good at blocking VEGF pathway, we’ve made real inroad in Overall Survival.  MTOR inhibitors are doing a good job; we kind of know where to use these, but we are getting better at it.  We have got to figure out why resistance occurs, and do something about it.  Participation in clinical trials is key.  We need to find drugs that kill the cancer cell directly.

QED

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Systemic Targeted Therapy for metastatic RCC in 2012

Kidney Cancer Association National Patient Conference

Dr. Eric Jonasch; MD Anderson Cancer Center

April 14, 2012

Systemic Targeted Therapy for Metastatic Renal Cell Cancer in 2012

I am going to talk as systemic targeted therapy for Metastatic Renal Cell Cancer, what we are currently using and how we are using it, and the science about it, and how that leads us to new ideas, moving forward. Although I can see people here benefiting from what we do it is not enough.

When we talk about kidney cancer, we cannot talk about just one disease type.  What I am going to talk about mainly is clear cell, and Dr. Tannir, my friend and colleague, is going to talk about the non-clear cell subtypes.

So what is ccRCC?  It is essentially a cancer that looks like this under a microscope, and it was called this, back in the day.  We more recently found that it has a mutation in the VHL gene (Von Hippel Lindau) in the large majority of individuals with and I also run a clinic where I try to marry the information we have about hereditary kidney cancer with non-hereditary kidney cancer to improved therapies.

Slide 2: This is not to scale; it is 213 amino acids long and for the scientists in the audience, that is mercifully short, and it also has three exons in or three parts, or easier to study than most, but obviously still hard to study.

Slide 3:

What it does, it essentially regulates how the cell reacts to oxygen.  Obviously oxygen is our life’s blood, we need oxygen to, we need water, we need glucose.  And our cells, if they feel like they hve enough need oxygen, they basically sit back and VHL will then take the transcription factor, it breaks it down  If you have low oxygen state, then the cell will say, “Help, I need oxygen” and the VHL will step back,  the transcription factors, HIF alpha and HIF beta are going to come together and you will get production of proteins, like VEGF which is a growth factor for blood vessels and some other things.  If you have a mutation or something how an inactivation of the VHL gene, you have essentially this ongoing process of these cells, now cancerous, saying—somewhat untruthfully—we need more oxygen, we need more blood, build me an infrastructure.

Slide 4

That infrastructure is as follows:  When we think of cancer we can’t think of cancer cells The cancer cells are in black on slide and in blue above, the stromal cells–the “glue” cells, and above those the endothelial cells or blood vessel cells.  This triumvirate plus other cells generate an organ—and it really is an organ—that we call cancer.  And when we use therapies, we are blocking specific areas there.

I’ll tell you a bit about the therapies we use now and that some of you are on, and what they are actually blocking.

 Here is some terminology you are about to hear, some jargon, as we talk about trials and therapies. 1) Progression free survival (PFS)—time it takes for cancer to start growing again and 2) Overall Survival (OS)—time it takes from start of treatment to passing of patient

 So the “blood vessel starving” are the five antiangiogentic therapies we currently have are listed here, and I am going to go through each of these in details.

We also have some up and coming drugs.  And the way these drugs work  (Slide 4 again) is by blocking the blood vessels. They try to kill the blood vessels that feed the cancer.  They don’t seem to have much effect on the cancer itself.  That is why you have experienced that we can shrink this down, but we can’t make it go away.  And what we need, and on our wish list, are kidney cancer cell-killing therapies for the future.

mTOR FDA approved;

Temsirolimus (Torisel)

Everolimus (Afinitor)

The mTOR inhibitors, of which there are two, Torisel and Afinitor, Temsirolimus and Everolimus.

What they do; they are actually working inside the cell both perhaps in the  cancer and blood vessel  cell.  And they are blocking particular proteins that seem to be up regulated, overexcited, in the cancer cell that give them a selective growth advantage.

There we have on the bottom, kind of a brown color, mTOR, which if it is overactivated, results in production of and more survival … for the cancer cells—which is shouldn’t have.  What Torisel and Afinitor do is to block that signal.

 

 

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Kidney Cancer Stage IV : My Round Trip & A Foreign Language

Nothing  catches your attention more than being told you have an incurable disease.  Quick translation= “you’re dead”.  All the words of encouragement, “we’ll do our best”,  “you’re a fighter”, “the doctors could be wrong” are  drowned out by the word “incurable”.

Doctors don’t like to answer questions like, “How long do I have,  doc?”, and patients don’t like to ask such things, in my experience.  But the internet and medical journals do give those answers, and rarely flinch when asked.  The only real stats I can remember about my diagnosis of kidney cancer, or its more melodic renal cell carcinoma, was that about 37,000 patients were diagnosed annually the US, and about 13,000 died annually.  Doing some quick math, I figured that I had three years, if I were lucky.  It is now more than eight (Now TEN!) years.

Being diagnosed with terminal cancer puts you on a new journey, say the more eloquent of us.  We welcome one another, remind them that this is all unknown, that it leads to a new country, the land of the sick, and certainly requires a new language.  Five year survival, times to progression, overall survival, ablation, and retroperineal are the new phrases you encounter. In addition to those darn Latin words of endless syllables,  that new language hijacks words we once admired, like “progression”.  Progression once meant to go forward, like passing into the next grade, or getting the vote, surely good things.  Not so.  Progression suddenly means that the cancer is on the move again.  Regression is the  good word in this new language.

We can’t even pronounce half the words that are thrown around in this new world, and don’t even know that all the body parts under discussion.  What is a collecting duct,  have I always had a venous thrombus, and what is the difference between metastases, lesions, masses and tumors? Is positive one of those words that means the opposite of what it was?

Just as this new language swirls around you, the alien disaster grows insidiously, betraying all you trusted, someone tells you with great earnestness that you must now be your own best advocate.  Isn’t the doctor supposed to be better at this than the patient?  Does no one else find it ironic that the same body which produced the tumor in ignorance is now asked to defend itself, to be skilled and capable of fighting off the threat to life and to choose the weapons to do so.  Am I now supposed to choose the meds and the techniques, advocate for one treatment over another?  Hell, I don’t even believe that this has happened to me?

In my older world, advocates had causes and clients. They went to councils and boards, court rooms.  To whom do I plead my case in this new world?  And where is the court of appeals, should I need a new trial? Can I get new representation?  Does my doctor even know what he is talking about?  Of course, “trial” doesn’t mean what it used to, anyway.  It’s more of a battle, with the weapons or medications being passed out to blinded patients by blinded physicians. Maybe half the weapons are dull or non-existent–placebos.  Welcome to this new world.

There is no Stage V, of course.  That is the ultimate “progression”, another form of “passing” that we talk about quietly and somberly.  I wanted none of that, didn’t want Stage IV, for that matter, and yet I had been on that grim journey for many years. I had no early warning, not seen the road shift beneath my feet, nor learned the new language. I didn’t know if there were fellow travelers. 

My cancer had probably started 8-10  years before my diagnosis, in some dark and poorly oxygenated part of my body, where some errant cell found a sweet spot to set up shop.  Cells became a tumor, which became a mother ship, sending off colonizers, who found endless new sites in my lungs, “tiny tumors too numerous to count”. That eerie phrase from the CT report lodged in my head.  No doubt, countless other tiny tumors, yet to be seen, were traveling throughout my body.

But now I am back home at what ever is called healthy, I may not be on any one of these apocryphal stages, hurling towards “progression”.  Mine has been a round trip, or I have passed “Go” and have been able to collect my prize for the meantime.  Of course, I do know that I am really just in a spur line along this journey. Sometime I am likely to be called back into the active mode again, but I will hear that alarm sooner than I did years ago, and I am now bilingual.

But eight (TEN!)years later, all the stats have changed.  Rather than the 37,000, we now are quoted 57,000 (61,000) newly diagnosed patients, and still with the loss of our beloved 13,000. There are more of us, but we die less efficiently. Can that also be “progression”?  How did I get home again?  That story will be told soon.

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