Category Archives: Lectures from Experts

ABSTRACT from ASCO & Impact for Patients: “Alterations in key clear cell renal cell carcinoma (RCC) genes to refine patient prognosis”

This abstract title reflects important changes about kidney cancer. It is not about “kidney cancer”, but clear cell RCC, with a  focus on changes or genomic alterations (GAs) in the genes.  The study goal was to see if patient the prognosis related to those GAs in genes that are found in RCC.  It describes ccRCC in a very detailed way–as to its gene expressions/changes.  (Abstract and Take-Home messages from Dr. Monty Pal are found below, with my comments to follow.

Session: Genitourinary (Nonprostate) Cancer Saturday June 2, 8:00 AM–11:30 AM
4516 (http://abstracts.asco.org/214/AbstView_214_229517.html) Alterations in key clear
cell renal cell carcinoma (RCC) genes to refine patient prognosis.

D Bossé, W Xie, Y Ged,et al
Take-Home Message
In this study of 308 patients with clear cell mRCC treated with VEGF-TKI therapy in the
first line, the researchers wanted to determine the prognostic value of genomic
alterations leading to loss of function. Genomic alterations in BAP1 were significantly
associated with a worse IMDC risk group and worse overall survival. Longer overall
survival was significantly associated with genomic alterations in KDM5C and PBRM1.
Significantly worse overall survival was reported in IMDC intermediate–risk patients
with PBRM wild-type tumors that also harbored genomic alterations in BAP1.
The researchers suggest that genomic alteration assessment may be predictive of
survival in IMDC intermediate–risk patients.

A prognostic study is about the likely progression of the disease, and the related risk factors.  With a more precise diagnosis of the disease, the prognosis will be better understood, which should guide treatments accordingly. (Sad that we still need prognostic studies vs comparative effectiveness studies!)

But first, a quick lecture on the background issues…

Patients might never know if their RCC subtype is clear cell (ccRCC),  papillary (pRCC) or chromophobe RCC (chRCC) until their tumor cells are seen under a microscope.  Until recently, most metastatic RCCs were treated similarly. Treatment was limited at best, with few options beyond surgery. When RCCs had spread, even surgery was not always recommended.  Diagnosis occurred when a mass was found, often fairly large, with about 1/3 of patients having metastatic disease.

It was wrongly assumed was that very small tumors  carried little risk, that they could not grow quickly and were unlikely to spread malignant cells. They could be ‘watched’. If removed surgically or ablated with radiation, there would be no real risk of spread and the patient needed no follow up treatment.

However, some small tumors are aggressive, grow quickly and spread to other organs. Surgery will not ‘get it all’, as the spread can occur well before the discovery of the mass. In addition, a “small” kidney tumor can be up to 7cm (2 3/4″) in size and have had years of silent growth.

Why do these tumors act so differently?  They arise from a mix of genomic changes in the kidney cells. Genomic alterations (GAs) vary in ccRCC patients, and those variations were thought to reveal aggressiveness and impact patient outcomes.

Earlier researchers found they could group ccRCC patients into categories based on the molecular characteristics of their tumors.  Those newly defined patient/tumor groups had every different Overall Survival (OS) statistics.  One subgroup had more aggressive disease, with OS of 2.5 years, while others had OS of over 8 years.  The more aggressive tumors needed to be identified and treated more appropriately. This abstract gives greater insight into those defining characteristics and the drivers of growth of those tumors.

Back to GAs–genomic alterations, or mutations/changes. Cells can change or mutate, due to age,  to family tendencies, or to environmental causes.  Cancer cells don’t follow the rules of normal growth, possibly due to these previously unrecognized GAs in the genes.  Most mutations in our genes do not cause problems, but some GAs in some genes drive tumor growth that endanger lives.

These genes –VHL, PBRM1, BAP1, TP53 and KDM5C–are often found in metastatic RCC. Each gene may have different GAs and at different frequencies.  Those characteristics define the tumor more carefully, and create greater risk of aggressive disease.  The abstract reviews the GAs and survival statistics in the patient population.

This is a study of 308  patients with metastaticRCC, previously treated with tyrosine kinsase inhibitors (TKIs), such as  Sutent and Votrient.  The patients were  grouped into ‘favorable’, ‘intermediate’ or ‘poor’ risk groups, a reflection of disease impact.  Their tumors were sequenced for GAs in the named genes.  Tumors have varying degrees of GAs within those genes, so were examined by those GAs and combinations of GAs. Then those GAs were compared with patient risks and their outcomes.

Those patients with GAs in the genes BAP1 and PBRM1 wt  had the worse OS.  Patients with GAs in the BAP1 gene had poorer survival, even if they were in the intermediate risk group.   The presence of GAs in three genes, VHL, TP53 and KCM5C did not seem to play a negative role in outome.  Indeed, the GAs with KDM5C seemed to improve OS stats.

What does this mean for the current patient with  metastatic ccRCC?  Perhaps a genomic analysis will give some guidance as to the aggressiveness of the disease, or reassurance that there to watch a tumor and decide the next step.  If the patient has alterations in BAP1 and PBRM1, which is associated with greater risk, he will need more aggressive care.

This information does not tell patients and doctors what treatment to use.  It does demonstrate the value of having one’s tumor sequenced to see the GAs, and help judge risk.  Those patients most at risk of aggressive disease may benefit from earlier treatment and  increased monitoring. Since about one-third of all patients not metastatic at diagnosis will indeed develop metastases, so that sequencing to discover these GAs would be a consideration for all.

This abstract gives a picture of the prognosis for the group of mRCC patients–not of any single patient–who have these gene alterations in theor tumors.  Other details will be found inthe complete study.  There may be comparisons as to how long the patients had been ill before diagnosis, the time until emergence of metastases, the length of time until TKI treatment, the length of response to the TKIs and time, if any, without treatment post the TKI until the sequencing.  There is no similar comparison to patients who were not treated at all, or who were treated with other agents.  The abstract does report a meaningful way to judge risk for patients with metastatic RCC with the use of gene sequencing, and that alone, can have impact on treatment decisions.

 

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Classifying Kidney Cancer by Its Biology; Good Looks Won’t Do It Anymore

Looks don’t matter in kidney cancer as much as they used to, as more information comes to us about the molecular or biological nature of the diseases which fall under the “kidney cancer” umbrella.  Can those important biological differences be seen in the pathology laboratory? Must we rely on next generation sequencing to determine which of the subtypes we might have?

Recent work by Dr. James Brugarolas and colleagues is reassuring.  Even as they found  new subtypes of clear cell renal cell carcinoma, they have also determined that these differences can be seen the pathology lab.

Why is this important?  So-called similar tumors may behave in quite different and more aggressive ways, so this is vital to understand the threat of recurrence from a very small tumor.  The affects monitoring and eventually will be helpful in drug selection.

An interview at the 13th International Kidney Cancer Symposium   October 2014

https://www.youtube.com/watch?v=tCoLwClv0tw

Cut and paste the above youtube address into your browser to be able to hear the lecture, while following along below.  The questions are in bold face.

Dr. James Brugarolas Discusses Biologically Classifying Kidney Cancer

“What we have learned with the development of next generation sequencing (NGS) is that no two tumors are the same. Every tumor has different mutations. Mutations are the drivers of tumor biology. With the advances of next generation sequencing, we have been able to identify and group different subtypes of kidney cancer, according to their mutation status.

Specifically, my laboratory discovered that the BAP1 gene is inactivated in 15% of clear-cell renal cell carcinomas. We found that BAP1 mutations are associated with high nuclear grade. That let us to hypothesize that patients who had BAP1 deficient tumors are going to have more aggressive tumors.

Furthermore, we found that mutations in BAP1 tended to anti-correlate with mutations in the second gene discovered by the Sanger Institute, by Michael Estrada and Andrew Futreal, the polybromo1 gene, PBRM1.

That led us to a classification that about 50% of the patients with clear-cell renal cell carcinoma will have PBRM1 deficient tumors and 15% of patients will have BAP1 deficient tumors. A small percentage of patients will have tumors that are deficient for both genes.

In a very productive collaboration we have had with Mayo Clinic, with Rick Joseph and Alex Parker, we’ve been able to determine that these different subtypes are associated with very different outcomes in patients. Patients that have tumors which are competent (not deficient) for both BAP1 and PBRM1 have excellent survival, whereas the cancer specific survival (CSS) is very poor in patients that have tumors that are deficient for both BAP1 and PBRM1. BAP1 deficient tumors have a somewhat intermediate survival phenotype, and the PBRM1 deficient tumors are similar to tumors that are competent for both BAP1 and PBRM1.

So we think for the first time, we’ve able to identify subtypes of clear-cell renal cell carcinoma that are likely to inform therapy in the future.

There is a gap between the discovery of the gene, to the determination of the clinical implications and subsequently to the therapeutic developments. That is because the therapeutic developments are going to emerge from the biologic understanding which we don’t have yet.

   How can improved classification of kidney cancer subtypes improve clinical trial design?

 That’s actually a very good question. So, what has traditionally happened is that a trial may be performed and one may find a group of patients–sometimes small, sometimes larger–that appear to do well with that agent. But if the group of patients is small, the trial is considered to be negative and the drug is abandoned. And I would say the problem is not that the drug did not have activity, it is that we were not able to identify the group of patients who appeared to benefit from that agent.

So the classification that we have developed and the identification of these different subtypes will pave the way to be able to do correlations. So then, when a clinical trial is executed when it is able to characterize better those subsets of patients that may benefit from the agent. For instance, as I was alluding to before, the BAP1 gene is inactivated in 15% of the tumors. It is possible that one of the drugs which has been tried in kidney cancer could have activity against that tumor. But there could never be a trial in that is positive that is being active in a small percentage of the patients, in 15% of the patients.

By identifying meaningful biological subtypes, we hope to deconvolute kidney cancer. It probably makes sense in trials going forward to do prespecified analysis of these genes that we now define as different biological subtypes–to be able to get at the question whether a particular treatment is having greater affect in one biological subtype versus the other. It is possible that it may not be that not all the PBRM1 deficient tumors that benefit, that are inhibited by a particular agent, there are other mutations. But it’s the beginning that which will lead us to identify those biomarkers and patients who are most resistant to a particular treatment.

 What is the significance of improved disease classification for kidney cancer patients?

 That is also an excellent question. These are discoveries that we and others have made over the last two or three years. The implications clinically have begun to be unraveled. It’s going to take significant effort and investment in research for us to go forward. We need to understand how loss of these genes, how mutations in BAP1 and PBRM1, are affecting processes inside the cancer cell, leading to kidney cancer development.

And in particular, we need to understand how BAP1, which is associated with most aggressive type of kidney cancer, is inducing that process. How is it that loss of the BAP1 gene makes the tumor be so aggressive? It’s only once we are able to elucidate the signaling pathways, that we will be able to identify targets for therapeutic invention.

On the other hand, we already know that for patients with localized disease, their prognosis is influenced biology of the tumor. I was alluding to this before, those patients who have removal of a tumor, localized to the kidney who deficient for BAP1 and PBRM1, they have a very high likelihood of recurrence in a short period of time. Those patients whose tumors are wild type for PBRM1 and BAP1 can do very well. (Wild type here means that the two genes are competent, or not deficient.)

Importantly, from the important view of translating these findings to the clinic, we have been able to develop assays, immunohistochemistry assays which are routinely performed in tumor samples at most institutions. (This is done in pathology labs).That allows us to very quickly determine whether we are dealing with the wild type tumor, BAP1 tumor, PBRM1 deficient tumor, or one that is deficient for both.

(Transcribed from the above YouTube video by Peggy Zuckerman. Any mistakes are mine alone, but hope this is helpful in understanding this approach to using gene sequencing in kidney cancer.

May 16, 2015)

 

 

 

 

 

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Filed under Genomics & Genes, Lectures from Experts, Medical Conferences, Rarer RCC Cancers, RCC Basics

Clear Cell RCC: Not as Clear as It Used to Be!

We struggle to understand what to do about our kidney cancer, but first must  exactly WHICH kidney cancer we have. Frankly, even the doctors are never too sure, and outcomes for patients with the “same” cancer varied widely.  No ready explanation was available, in those bad old days.

Treatment decisions were easy, but not effective for most, when every kidney cancer patient was treated the same.  Patients had surgery and were sent home. Those with smaller tumors, under about 2 inches, had little or no follow up.  Those with larger tumors might be monitored more frequently. Mets might emerge, and maybe more surgery would follow, but no meds were available until 1992 when high dose interleukin was approved.

Patients who presented with metastatic disease were not even offered surgery, being told that there no value to removing the primary!  An ongoing “controversy” was whether there was value in a nephrectomy when mets were found.  Too bad, so sad. (If your doctor is telling you that last bit, you need a new doctor. Now.)

Then came the recognition that there were different kidney cancers, variants and subtypes, all based on the look under the microscope.  Conventional kidney cancer became known at clear cell, and a mix of new subtypes were named.  We now hear of clear cell, papillary type I and type II, chromophobe and more.  Sarcomatoid RCC can arise from any of these types, confusing things and reflecting a more aggressive course for the patient.  Most are sporadic, out of the blue, but others have an inherited component.  Again, making things trickier yet!

Ironically, the trials in the late 80s of high dose interleukin which led to the first FDA-approved treatment, included all the above types. The relatively low response rate in this trial may have been due to the rarer RCC types, unlikely to respond.  This minimized the use of HD IL2, perhaps to the detriment of many patients. The targeted therapy studies often excluded the rarer types, hoping to boost response in a more limited group.  Few trials really test agents appropriate for the non-clear cell types, so the guessing game for them is really the norm.

With that background, there was still wide variation in the outcomes for clear cell RCC patients.  Some patients with small tumors, found at an early stage, can have very poor response to treatment.  Many such patients have long-term survival, easily over 10 years, while others who “seem” similar, succumb to their disease quickly.

Why is this the case?  Short term survival vs long term survival, aggressive appearance of mets vs slow-growing, good response to treatment vs minimal response?  Why would the same disease be so different?

Easy answer.  It is not the same disease.  Clear cell RCC, that so-called conventional type, maybe 75% of all the kidney cancers, is not really one disease. Clear cell may be subdivided into four separate types, each with its own survival pattern–and all due to its early genetic drivers. Researchers have been able to sort out the genes, compare the mutations, deficient or over-expressed, and find them in tumors of patients who were treated and followed over many years.

Just as there is no magic bullet, no one medicine that fixes everything, there also seems to be no one poison bullet.  It is not just one thing that goes wrong, one nasty gene breaking the DNA rules, but a combination.  And there will be more combinations.  This is like the typical disaster stories, where it is not just one thing that goes wrong, but a series of events and changes.  Each one of the series might not create a problem, but in combination and with the right timing, there is a perfect storm–the very aggressive tumor.

Without getting too technical, clear cell RCCs can have a mix of genes that mutate.  Recent studies have shown that two genes in particular, BAP1 and PBRM1 can either be sufficient (or competent or positive) or they can be deficient in their expression.  There are four possible combinations, positive for both genes BAP1 + and PBRM1+, negative for both genes BAP1- and PBRM-, and combinations with the BAP1+ and PBRM-, and the reverse, BAP- and PBRM+.

Why does this matter for the study patients? All of them had localized disease at the time they were diagnosed and all were clear cell patients of similar age.  BAP1 was mutated/inactivated/deficient in about 15% of these patients, and that mutation was associated with high nuclear grade, or a more aggressive type of tumor.

About 50% of clear cell patients had the PBRM1- tumors. Others had a mix of one gene positive and the other negative. Mutations of BAP1- and PBRM1- were rarely found together, but that combination predicted poor survival, in one study of just 2.1 years.   Having just the BAP1- had an overall survival of 4.6 years median, while the deficiency of PBRM1 (-) had an overall survival of 10.6 years.

This shows that clear cell RCC is really not one disease type, but four.  Most importantly for patients is the knowledge that these varying mutations may respond to different medications.  Also, these mutational differences can be seen in immunohistochemical or pathology tests, which can give greater guidance to treating physicians.

Coming soon is another lectures by Dr. Brugarolas, so watch this space.

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Filed under Genomics & Genes, Lectures from Experts, RCC Basics

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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Filed under KCA Conferences, Making a Plan, Targeted Therapies, Your Role

Clinical Trials for Renal Cell Carcinoma; Dr. David McDermott; Dana Farber Harvard Cancer Center

I am presenting for Dr. Bukowksi (of Cleveland Clinic Taussig Cancer Institute) and this is his outline.   It is not so much about novel therapies, but about clinical trials, why they are important.

Clinical trials, what’s in it for you?  We talked about it for the field, but what is in it for the patients who might want to consider a trial?  What is a clinical trial?

“A study conducted to allow safety and efficacy data to be collected for a health intervention such as a drug, device, or treatment protocol”, as per the slide.

They are designed on a certain ethical code of conduct which we follow very closely.  They are monitored very closely, followed by people, both internally and externally, the FDA and IRB, the Institutional Review Boards at our institutions.

This  list– I thought this was pretty funny– that Dr. Bukowski came up with is from a Persian physician, on the ways to conduct a clinical trial, from 1025 AD, a thousand years ago.  I don’t know how many clinical trials were done a thousand years ago, but I thought the last one was pretty good, “The experimentation must be done on a human body, for testing on a lion or a horse may not prove anything about its effect on man.”  We talk a lot about morbidities or complications on people on clinical trials; I can’t imagine being the investigator on any lion trial! Probably higher risk for the investigators than the lions.  I’m glad we made advances in the last thousand years.

This is one of the more famous clinical trials, given by James Lind in 1747.  He was given the task, and first to show that citrus fruits could cure scurvy.  He did what was like a randomized trial, comparing the effects of various acidic substances, citrus fruits or cider– gave them to sailors with scurvy, essentially proving that giving oranges and lemons can give quick recovery in patients with vitamin C deficiency.  He is one of the founding fathers of our field of clinical investigations. We’ve come a long way since then.

As far as types of clinical trial, some are conducted in different ways. Some are what we call observational, meaning we collect data that other researcher use to study patterns, to study outcomes over the long period time, things like risks for heart disease.  For this group, we often do something for patients, usually with a device or a therapy, and this usually compared to a group receiving no therapy, no treatment, or commonly, the old standard of treatment of care.

There can be many different purposes for trials.  Some can be for screening, some are preventative, which we haven’t talked about much yet, but can improve the way we diagnose kidney cancer. So there are many different types of trials.

You want to ask, “What phase is this?”  The reason that is important is that each phase of testing has a different goal.  I will focus on the middle ones here; Phase I often focuses on the drug safety. It has  traditionally been about, “What’s the right dose of the drug?  What’s the right schedule for the drug?”  Traditionally, Phase I trials have not always been great for the patients, as the main focus is “What’s the safest way to give the drug?”, not whether the drug is effective. They were often left for patients with fewer or other options, when everything else had run out, you would consider a Phase I trial.

But nowadays, Phase I trials are changing somewhat.  They are often not open for patients with just any kind of cancer.  They are open for patients with specific kinds of cancer, because there is already some sense that this drug looked interesting in the laboratory, that it might be effective for a specific type of cancer.  W aremore focused in that regard.  We are also testing patients for certain tumor characteristics, so getting a sense, not of what kind of cancer they have, but what kind of tumor do they have, what kind of genetic changes are going on in that tumor.  Most importantly, some phase I trials—once they get the safe dose—are doing what is called “dose expansion”, where they take patients with specific tumor types and treat them all with the same dose. This is essentially doing a Phase II trial within a Phase I trial, though a smaller Phase II trial.  In many ways, there is an advantage on the being on that kind of trial, in my admittedly biased opinion, because you know you are getting a drug that has shown in many cases some sense of safety and activity. It is certainly something you should consider, not necessarily right off, just because your doctor wants to consider you for a Phase I  trial.

Phase II trials’ main focus there is the effectiveness; how effective is the treatment?  They usual focus on some single cancer type.

Phase III trials are a more comparative trial.  It’s comparing something that is new to an older or the standard treatment.  For many years, the “new” was really no better than the old, but one of the things that more recently, is that a lot of the new has been better and we often have had a sense that it was better, before we got to confirm it in trials.

One of the uncomfortable things about a Phase III trial, from a patient’s point of view is the randomization.  It makes them very anxious.  You lose a certain amount of control, both the physician and the patient, about what you are going to receive.  So a lot of people choose not to go on a Phase III trial because they are uncomfortable with that process.  The way I like to look at, not as a patient’s perspective, even in a randomized trial is that you get a 50% chance at trying a new agent earlier.  That may not be worth it to you, but it’s worth a discussion, a consideration as you go through treatment.  There often are also trials that come after the drugs has been approved, like expanded access trials, where they offer it to patients just to test further questions, safety, for example.

We talked a little bit about clinical trials, and some of the caveats, about randomized trials and how that can throw people off.  Like randomization: It turns out that this is the only way we know if a new treatment is effected. As many flaws as there might be from a patient’s perspective, it is here to stay. At least for the time being, we are going to have randomized trials.

One other concept that often also throws people off is whether the trial is blinded, that is, where the researcher and the patient may not what the patient is getting.  Why is that?  The reason is that because if you know what someone is receiving, you might make judgments that bias the outcome, both on the patient’s side and the physician’s side.  A lot of people don’t like not knowing what they are getting.

PLACEBOS

The one thing that throws the most wrenches into this is the whole concept of a placebo as a control arm, and unnerves a lot of people for good reason.  You are going to  to be told if a placebo is involved, number one, for sure, up front. Now that we have effective drugs, placebo-controls are less likely to be acceptable options.  Meaning, they are only acceptable if there is no standard treatment, so 5-6 years ago, when there was no or very few standard treatments for kidney cancer, we relied on placebos.

Now these are being compared to active treatments.  So you are either getting active treatment A or active treatment B, comparing it to a new treatment.  Going forward in kidney cancer, there will probably be fewer and fewer placebo-controlled trials.

Here’s a list; you’ve seen this before; all the important trials that they have done in the last ten years. The important thing about this is that is patient involvement that has made this progress possible.  This is a look at 8-9 trials that have enrolled 4000-5000 patients.  It is quite a long list of progress, made only by patients with a willingness to so, so it is important to encourage people that you may communicate with online or in your email to consider participation. It is only through that participation do we make this kind of progress.  Clearly we have more progress to go.

So summarizing our recent advances, to show that we can shrink tumor in 10% up to 50% of patients in these newly targeted agents.  As Dr. Jonasch was talking about, we can surely slow tumor growth which leads to lengthening of survival.  Patients are living longer, Hutson says 3-5 times longer.  My patients are living years longer than they used to in the past, but we are still not receiving enough remissions.  We need to work on getting remissions, once the treatments have stopped.

We talked about participation, we need to do that to improve outcomes.  We need to better understand the biology of kidney cancer, as Dr. Jonasch was talking about, to identify patients before they get treatment, and to assign them to treatment that is likely to help them. It is only through that–not just clinical research, but also laboratory research– that we will be able to do that in combination.  We need to increase the funding for those endeavors, as it is rather expensive, at a time when the NCI’s budget is fairly tight.

You hear a lot about personalized medicine in the treatment of cancer, but we are not yet in the era of personalized medicine for kidney cancer.  We are making certain decisions, but they are based on fairly rough guidelines, but we are making decisions based on whether a patient has been treated or untreated.  We are trying to assign to patients to certain risk categories based on certain features of that suggest a good or a poor prognosis.  We are making decisions, as we talked about earlier, on whether a patient has clear cell or non-clear cells, but these are very rough sort of guidelines.  We need better ones, obviously and we are hoping to come up with better ones, based on the patients’ own genetic profile and the profile of the genetics of the tumor.  There is a lot of work going on in that as we speak.

Recently reported trials; these are trials reported in the last year.

Not all trials are positive.  The first is called the Renal Effect Trial, randomizing patients to either prescribing the intermittent dosing of Sunitinib versus the continuous dosing of Sutent.  The hope was that giving the drug at a lower dose continuously that the treatment would be more tolerable or more effective.  It turns out that there was no difference, so they could be used interchangeably.

There was a second trial with Sorafenib, where they added on another anti-angiogenesis inhibitor, in hope of improvement with the standard drug, Sorafenib.  It’s the trial in the middle there, and unfortunately, the additional drug did not improve outcomes to the Sorafenib.

The last trial on the bottom, that both Dr. Hutson and Dr. Jonasch mentioned was a Phase III trial, once again a randomized trial that comparing—not a placebo—but a standard of care, Sorafenib to a new therapy, axitinib, which proved clearly that axitinib was a step forward.  It may be a small step forward, but it is important for our patients.  That led the FDA to approving this new, hopefully, second generation anti-angiogenesis drug for our patients earlier this year.

So what’s coming?  Hopefully, drugs that are less toxic and more effective.  There are a series of Phase II and III trials that are coming close to reporting their results you will be hearing about them in the next year.

Their names you see here:  COMPARZ, RECORD 3, TIVO1, you’ve heard a bit about, TORISEL 404.  We talk a little bit about these, what we can expect from these trials.  We can also talk a little bit about targeted immunotherapies, vaccines and ultimately, combinations that might make sense.  All these are being tested and in the next year, we’ll know a lot more.

There are several trials, trying to improve upon Sunitinib, which is the most prescribed treatment for patients with metastatic kidney cancer in 2012.  The COMPARZ trial is comparing Sunitinib with Pazopanib, which is Votrient.  The makers of Votrient would hope show that it is as effective as Sutent, and perhaps less toxic.  We’ll see that result later this year.  Obviously, drugs that are less toxic are worth developing.

The other trial looks at the proper sequencing of the RECORD trial.  Should you start with Sutent and move to Afinitor, or start with Afinitor and then move to Sutent? We should get some information on the proper use of Sutent, hopefully, with the RECORD 3 result

We mentioned the AXIS trial which compared axitinib to Sorafenib and led to Axitinib’s approval. That was a step forward.

Hopefully there will be another step forward in the second line setting, which is this new -1, a second generation of anti-angiogenesis inhibitors. This TIVO-1 trial which Eric (Jonasch) mentioned  targets a new, more specific antiangiogenesis inhibitor , comparing Pazopanib to Sorafenib, showing it was more effective, so once again, we are coming with better agents than five year ago.

Another important trial will compare an mTOR inhibitor to Sorafenib again, Torisel to Sorafenib standard and to answer the question, when you fail a prior treatment like Sutent, what is better—to give you a another drug like Sutent, or to give you a completely different approach—which is the Torisel drug.  We’ll be learning a little bit more about the proper sequencing of these agents.  All of this information should be available coming soon.

The Tivozonib data will be presented at ASCO in June and hopefully the Torisel data will be presented later this year.

Combinations of drugs; most oncologists think that if one drug is good, two have got to be better.  There have been a lot of combination trials done this far.  Most have been, I must say, somewhat disappointing, and we will talk about why that is.  Hopefully, as we get less toxic agents, we will bet smarter about putting these things together, and we will make some progress.  These are some of the drugs that have been used in combination.

Laboratory trials have suggested these: we don’t just do these willy-nilly. Laboratory studies have often shown that two drugs are better than one, but there are several important issues.  One of these is cost.  You all know that these are not cheap.  The other is toxicity, and so far, most of these combinations have proved pretty toxic when given together.  Here are two trials that are looking at a blood vessel strategy with mTOR inhibitors.  The RECORD 2 trial looks at Bevacizumab and Everolimus together versus the standard of Bevacizumab and interferon; the INTORACT trial looks at Bevacizumab and Temsirolimus together.  These are both large trials that will give us the answer to whether two approaches to attacking the cancer  better than just one at a time.  We’ll see that going forward.

As you know, as we talked about things today, that none of/very few of these drugs produce complete remissions, and we obviously need second- and third-line treatments.

 

There are a couple of trials accruing that will give us some answers to that.  There is another antiangiogenesis inhibitors, the TKI-258 (references  on left), and it is in phase III trials, once again comparing to Sorafenib, so that might be a step forward as well.  Looking at this Phase 3, looking at this Cooperative Group Trial, looking at combinations, adding Bevacizumab, hoping that will aid in outcomes with what Everolimus does. We’ll see.

We’ve talked about vaccine treatments, and I alluded to one trial, the ARGOS III trial, looking at combinations of vaccine and Sutent.  It is more than one trial, it is the IMMATICS trial on the right,; it looks at another peptide vaccine, also in combination with Sunitinib.  Hopefully it will lead to more durable benefit with this drug.  It is great that we are in large Phase III trials, as this will give us answers, but the answers are still a long way away, as these trials are still enrolling patients.

We mentioned the PD Antibody earlier.  This is one of the more exciting ones of the targeted therapies being developed.  Two things I did not mention this morning that I want to make now, is that this drug will soon be entering Phase III trials.  It’s moving pretty quickly, and hopefully Phase III trials will open later this year, and if positive, might lead to the drug’s approval.

But just as important, there is more than just one PD or PD L drug in development.  These are five separate companies, all of whom have decided it is important to find different way to block the “barbed wire” that I talked about, that protect cells from the attack by the immune system.  You will hear more about these agents, not just in kidney cancer, but in other tumor types as the year goes on.Chris Wood covered this very well earlier, so I won’t address that, but we are also doing clinical trials with drugs that have been used with Stage IV patients, we are now using those with Stage II and III patients.  And as he (Wood) said, it will take several years before we know if it will delay cancer from coming back after surgery, or will prevent cancer from coming back after surgery—there’s a big difference with those two.  We are several years away from knowing those results.  But the great news about these trials is that they are accruing well.  Patients have gone on them very quickly, much more quickly that we expected, though the drugs may have issues for the patients, side effects…..we will have to see about the effectiveness.  The patient community if very motivated to go on trials like this, so hopefully as we get better drugs, we can test them in patients in the early stages of kidney cancer and prevent recurrences.  That’s where we can have a huge impact, preventing the need for treatment for Stage IV cancer.

So, in closing this is obviously one fundamental question for folks who have not considered a clinical trial.  Obviously I am biased, incredibly biased, as it is what I do.  I think it gives you access to cutting edge approaches.  Obviously the newest thing isn’t always better, and sometimes it is harmful and we’ve seen multiple cases of that.  But I do think you get access to things sooner if you consider trials.

And I do think we are getting better, as I mentioned, picking treatments than we were ten years ago, and also picking patients for those treatments.  We are a little bit smarter.  We are having more positive trials.

But all that being said, the participation of patients in the US in clinical trials is still less than 3% of patients.  So when you think about it, I can sit up here all day and talk about all the things I want to do, and Eric (Jonasch) has great ideas, and Tom (Hutson) has great ideas, and Chris Wood’s ideas are OK (smiling), but we can’t do it without participation and convincing people to come and sacrifice, as there are costs to travel and risks .  It takes a lot and really requires a mobilization of the whole kidney cancer community.  I hope that this will increase the willingness to participate in clinical trials to get the message out about why it is important.  There a lot of reasons why you might want to consider it, but people ask, What else is in it for me?”  I know what is in it for me, and for the field, but what else is in it for me personally?”

There are some people who think that the care on clinical trials is better.  You can argue that back and forth, but you are certainly followed much more closely on a clinical trial that you wouldn’t be if you were not on a trial.  You are not only being watched more closely for side effects, you are watched very carefully to see if the treatment is working.  There are a lot of rules set up to protect you, not only from the side effects, but from ineffective treatment.  There are rules by which we have to remove you from your trial if it is not in your interest.  Most importantly, you can always stop at any time, once you join a clinical trial.

The other question which is a little bit harder to address is whether patients on clinical trials do better, and he has some interesting data

data that was presented last year.  This is looking at 238 phase III clinical trials of all cancers done in recent years.  When you look at this slide, and it’s a little bit complicated, I didn’t want to get too much data in it, but it is kind of important..

For the 158 trials that reached their goal, where they reached the sufficient number of patients, Sufficient Accrual, that was 2/3 of phase III trials. So not all phase III trials reached their goals of accrual of patients, which is a problem.  But of those that did, most of those trials showed positive results, in fact, 143 of 158 had positive results.  There were some that had negative results, closed early, or had side effect of toxicity.  But it was a relatively small number, only 15% on this slide.  The highest reason for trials not succeeding was that they did not get enough patients on them.

This makes a couple points.  One, we’ve got to get more patients on trials, so we can answer these questions.  Second, a lot of the trials that we are doing help advance the field, but we think help the patients who go on them.  That would be hard to prove, but it is certainly worth considering. There may be some advantages for you as an individual when you are considering going on a clinical trial.

 

So in conclusion, clinical trials advance our knowledge and  have improved outcomes in kidney cancer.  It has been a great effort by many patients.  Six thousand patients have gone on these trials that we have talked about over the day, not only improving outcomes for themselves, but also for future ways we treat patients.  Coming up with better way to treat patients is only going to happen with research.  We need to keep working on it, to define new approaches, we need to extend treatment earlier in disease, and we need to focus on patients who are unable, or don’t qualify for trials.  We need to do a lot more work in that area, but hopefully, in partnership we can make advances, like we have in this last ten years.

End of Lecture; Questions from patients and caregivers follow.

Questions;

ACOR list member has asked about XL 184.  How optimistic are you about XL 184 having activity in bone lesions, as well as soft tissue lesions; also, as far as imaging, she would be concerned about masking of bony lesions on imaging.  On recent studies, ie, questions whether bone scans are the best measure of activity of XL 184.

That is a pretty sophisticated question, and in my earlier talk, I got a questions about XL 184 and I think this.  In kidney cancer, it has only been through Phase I testing, so I think it is a little early to know how active it is.  But there are really people in our community that really want to study it.  The focus is not only the VEGF but the protein that Dr. Jonasch mentioned, that MET protein which is thought to be an important driver in all cancers, and kidney cancer.  Certainly we want to study it.  It’s been tested mostly in prostate cancer, and they’ve seen some impressive results. We’ve seen that in prostate cancer, but whether we will see that in kidney cancer, that remains to be proven.  That would be an advance, something that would control bone metastases. That would be exciting, since a lot of our drugs fail in bone. But it would need to be tested.  I couldn’t agree with that more.  How well it will be tested, that remains to be seen.  Dr. Tannir may be talking of this class of drugs in his talk.

 Soft tissue metastases, any activity in that?  I know we’ve seen activity with the bone mets, but soft tissues?

Answer: It is to early to say that we have seen that, but that is certainly the story in prostate but we don’t know yet in kidney cancer.  But you will see a presentation at ASCO, where you will get a sense of how well it’s working in kidney cancer, but it’s going to be a very small trial.  We need a much bigger trial.

  This is a more general question, and I never hear anything about it.  Is anyone collecting data on your outliers, those people who survived the interleukin 2, IL, or data, anything to see if there is something homogeneous about them or any attributes?  I just never hear anything about this.

DO you mean people who can’t go on trials, or people who do really great?

 Those who do really great, those with long PFS or OS, people

There are people who are thinking about those questions and there are more often cases, where when people present, their tissues or blood and tumor stored for analysis so we may be able to do that kind of study in the future.  There are people who are looking at genetic predictor of response to treatment but right now there are no great predictors of response to these agents.  We need to do a lot more work on that.  We don’t understand why there are great responders—yet.  We have the capability of learning about that now we are collecting information.

 I just wonder if it is lack of patients or lack of money, if there is no big drug involved.

Any research will say there is lack of money, we could also do with more money.  There is also a lack of insight.  If we have the information, can we tease out what it is important.  I think Dr. Jonasch is going to save me with an intelligent answer.

Jonasch:  I don’t know if it will be intelligent, but it is an answer!  Anderson has an unusual responders program, and what is to be done, and Dr. Tannir and I are both participating in that.  We are taking those with outstandingly good and outstandingly bad responses, and we are performing sequencing analysis to get clue to determine what exactly makes those people different.  Hopefully I am getting my data back in the the next month or so, with individual are treated with Sunitinib.  So it will give us some ideas , to understand those differences.  So, no answer yet, but work underway.

 I don’t want to be morbid, but want to understand.  You have just said about sending tissue, is that at the end of your life or?

It’s usually at the time of diagnosis, so Anderson is great example of this.  They will ask you after the tumor is removed, after Dr. Wood removes it, can we  have a piece for our tissue bank?  They will save it, save it in an impersonal way, and they will use samples from your body, not just the tumor, your urine or your blood, things like that and track your outcomes, along with a large number of people.  By donating that tissue upfront, it is a lot more useful and we can get a lot more information about your tumor if we can get a fresh piece of tumor.  We like fresh tumor.  We’ll take anything, but fresh is better.

 I am asking a question which may have explained a bit earlier,how the patient is handling side effects and how that puts a greater responsibility on the patient.  How is a patient who is not able to come to a place like MD Anderson or these other center.  How is a patient able to help guide or cooperate with his local oncologist and handle this massive amount of information and differentiate whether he is getting the best treatment possible.

OK, that is a complicated question,  For the most part, now that we are 5-6 years into these new agents, most oncologists are making good treatment decisions.  In the case where you are not sure, you’re unsure, you can always ask, “Can I get another opinion?”  I think most oncologists don’t feel awkward about that.  “Is there someone you can call to ask about my side effects?  Is there someone you might send me to for this next treatment decision? These days, the good news is that you can end up receiving a lot of your treatment close to home, since these drugs are approved, but getting a confirmation is sometimes helpful, just for piece of mind.  Most oncologists that I work with are pretty comfortable making that referral.  Going through your doctor is a lot more productive than going around.  That’s my personal experience.  They get experience, they work in tandem, which is better than losing track of the local person.

QED

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Filed under Immune Therapies Old & New, KCA Conferences

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.

S

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?”

58

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.

END OF LECTURE>

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.

SAFETY RESULTS; ALL PATIENTS
For the entire group, MTD (Maximum toxic dose) was not reached at doses of 1, 3, and 10 mg/kg
There was no apparent relationship between drug dose & AE (adverse effects) frequency
One treatment-related death 
Grade 4 drug-related pneumonitis                                                 Slide 20

The main reason to do a phase I trial is to test the safety of the drug. This drug was found to be relatively safe, and we got up to the highest dose without getting into serious side effects.  There didn’t seem to be a relationship between the dose and the side effects, which was good. There were still 10-15% patients who had serious side effects. In this group of kidney cancer patients and there was one treatment-related death, due to an inflammation in the lung that was probably contributed to by the drug.

  SAFETY RESULTS; ALL PATIENTS

Any grade, drug-related (investigator attributed*) serious AEs (SAEs) occurring at a frequency >1% in the entire study group (n=126)
            Total with an SAE=11%
            Investigations=3.2%
            Endocrine disorders=2.4%
            General disorders and administration site conditions=1.6%
            Hepatobiliary disorder=1.6%
            Neoplasms benign, malignant and unspecified=1.6%
            Respiratory, thoracic and mediastinal disorders=1.6%                         Slide 20a

 This trial of 126 patients was a much larger group and not just a kidney cancer trial with five cancer types in this trial. There are now 300 patients in this trial, and we’ll get more data in the next several months.  But in general the safety population is much larger than the efficacy population.  The main point here is that serious adverse events occur in about 11% of all patients, much less than in HD IL2 and CTLA-4.

What did we see in terms of effectiveness?  For the first 16 patients analyzed, we saw five partial responses (31.3%), and three patients (18.8%) with stability that lasted over six months. About 50 % of patients were getting some clinical benefit with this antibody. Once again, a small number of patients tested.

Here is an example of the patients we studied, a young man who was diagnosed in 2009, received IL2 and progressed, received Sutent and progressed, had disease in multiple places, including the kidney and the bones and lungs. You can see the before and after pictures after receiving two courses of treatment of ipilumimab with a significant response in the lungs, which is ongoing therapy after two years.

We’ve also seen responses in some unusual places.  One place that a lot of our VEGF targeted patients fail is in the bone. This is a patient, before and after, who had a response with a bone metastases you can see here (left scan), and actual healing bone (right scan), just a year later with treatment.  That’s certainly an encouraging result for us.

How long do these responses last?

For this admittedly small group, it looks like the major responses for a majority of these patients who had a response, that response lasted over a year.  Most who had a response still have that response at a year.  Whether that response will continue or stop, when the drug is stopped, remains to be seen. That will be a very important question. But the good news is the patients can tolerate this treatment for a year or more.

In summary, the PD-1 antibody concept is very early, but it has displayed reasonable side effects at all doses we’ve tested, and we seen some anti-tumor activity in some patients with kidney cancer.

PD-1 Antibody Summary
At this EARLY point, BMS 936558 has displayed manageable side effect at all dose levels tested
Anti-tumor activity observed in a small number of patients with RCC
            Responses may be durable?
16 patients added to this cohort-ASCO 2012
Responses in NSCLC
Trials launched in 2011 in RCC:
Dose finding Phase II study in patients with prior therapy
Biomarker Trial
Combination RX + VEGF TKI (Phase I)

Were these remissions, i.e., durable, or just responses?  Will the patients’ tumors grow after we stop the drug?  We don’t know that yet, but we’ve added 16 more patients to the study. We will present data at ASCO in two months (6/12), with more information on this anti-body soon.  It is important to note that with this drug and for the patients on it and for the field of immunotherapy for cancer that we are we seeing responses for kidney cancer and melanoma, where we’ve seen immune responses before. It is quite important also that we are also seeing responses in lung cancer. Should that be true, that will bring a lot of energy into the field going forward, as lung cancer is obviously a much more common illness, with very few options available.

There were a lot of new trials launched in 2011. We’ll have a Phase II trial in 2012, including multiple doses, to find the best dose in this treatment and also in combinations with other drugs like Sunitinib to find the best combinations.

So for those who say, “Is there a role for immunotherapy for RCC?” I would say there’s been a lot of progress over the last 30 years in the field of immunology, and we can now better target immunotherapy, and it’s worth preserving.

Is there a role for immunotherapy for mRCC?            There has been progress in the field of immunology in the last 30 years

            Immunotherapy can be “targeted”

            Immunotherapy is worth preserving                          Slide 25

There is a role for immunotherapies shown by survival curves like this; this is from the SELECT trial mentioned before.  These are patients who responded to treatment, now out three years, off treatment. The 13% percent of these patients, 16 patients have that benefit which really achieves the patient’s goal, which is worthwhile to try to get for more patients. It is proof of principal that we can do this, but we need to do it for lots more patients.  If we work on this, hopefully we can achieve Dr. Wood’s goal of more cures for kidney cancer, with targeted immunotherapy.

QED

Audience: Does the pathway of the targeted drug therapy have any impact on whether or not immunotherapy would have any effect on tumor growth or not? Different targeted therapies have different modes of blocking pathways.  Would that have impact, or has your research shown any impact on different pathways.

 Mc Dermott: “That is a very good question and not simple to answer.  Many of the treatments I talked about, like the cytokines, like IL2 or interferon or CTLA-4 work on the patient’s immune system-we think ONLY, only, meaning they are boosting the immune system to an established cancer.  For reasons we don’t completely understand, that is effective in some patients and not in others.  In the case of the PD-1 antibodies, they may be acting on the immune system, and may act on the tumor as well.  There is some evidence of that in the early research, as I mentioned with patients who have this barbed wire on the surface of their tumors, or have this pathway activated, or when this pathway is on, they may be more likely to respond to this approach.  Meaning, when the barbwire is up, and you can block its activity, maybe you can lead to an effective immune response.  And what that may say something important about the pathway, but it may also say something about the immune system’s response.  The barbed wire, we think, is up, as a reaction, a survival mechanism for some tumors. That is one of the reasons that cancer is so difficult to deal with, that there are so many different ways the tumor can evade the treatments. That barbed wire, that PD-1 may be one of those protection mechanisms.  So that means tumor turns on, the barbed wire is up when the immune system is there, you can’t kill it, but you can block the barbed wire, take these immune cells are right there and it can kill the cancer.  This may explain why some patients have a benefit and some don’t.  And we are now looking to see, if your tumor has barbed wire, whether you are more likely to respond to treatment.  There will be a lot more information about that in the future.  Good Question.”

 Question: I wonder if you knew if there was a clinical trial going on for prostate cancer, believe it is called XPl 4(sic), and its for bone mets, and if you knew anything about it’s work with RCC.

 McDermott:   “Re this med and RCC,I don’t treat prostate cancer, just melanoma and kidney cancer.  Is the drug you are talking about XL 184?  This is a drug that is in early trials, and maybe Dr. Jonasch will talk about it and similar drugs.  These drugs work in the blood vessels to attack the cancer.  They target two proteins, VEGF, which you’ll hear a lot about, and another protein which is important, C-MET, called MET inhibitors.  There has been interesting activity in prostate cancer with this drug in trial, and a very small trial we participated in Boston with this agent with kidney cancer patients.  You will see more info on this drug at the ASCO meeting in June and the info will be public on May 16.  ASCO publishes all its info, so you will be able to get your hands on the results from that very small trial in a very few weeks, which is good.  It’s a drug that has promise, but it has some side effects that need to be managed.  The fundamental question here is for the kidney cancer advocacy community, is it going to be tested in kidney cancer?  We are still not definite yet, but we are pushing to test this class of drugs in kidney cancer, this particular drug. We are pushing sponsors to do trials, but they are most interested in prostate cancer.  When those trials are to start and with kidney cancer, we are not entirely clear.  We need to push them to keep developing these interesting drugs for our patients.”  

 ME:  This is an extension of the question, as to how you choose the best patients who have the best chance of responding to IL2.  Does the histology or the pathology, and frankly I don’t know the difference between the two, have a major impact, and can you expand on that?

 McDermott:  “Yes, I may have gone too quickly on that.  We thought the answer was yes, and when it comes to big differences,  clear cell versus non=clear cell, it does, meaning when patients come to us, non-clear cell cancer for IL2, we will say to them, ‘It’s not going to help you, or the chances are so small, that the harm or potential harm outweighs the help.’  So to answer one of your questions, non-clear cell histology, which is simply a medical term for ‘What does this thing look like under the microscope?’.

 For non-clear cell histologies, we don’t offer IL2.  Whether one of these newer immune therapies work for that class of patients, should be tested because there is hope.  That is why I mention the lung cancer story, because if it can work in lung cancer, it might in one of these less common kidney cancer types.  It may work for many other forms of cancer.  So that is a hopeful thing and exciting.  But to take it a step further, while we thought clear cell cancer was more likely to benefit, we also thought it was that certain types of clear cell cancer were likely to benefit.  That is what we tried to prove in that trial, but we couldn’t prove it.  Doesn’t mean it wasn’t so, we just couldn’t prove it. We haven’t improved out selection ability based on looking under the microscope in ways that we had hoped.  We can do it a little bit, and that’s why the response rate went from 14% when the drug was approved to 25 % today, but it’s not enough, so patients don’t have to go through the side effects if they are not to benefit from the treatment.”

 Question; I don’t know if I know enough to ask a coherent question, but this is related.  Why would it be that certain tumor types or subtypes would respond to IL2 or not?  Is it because their profile of cell surface markers that let the immune system targets them better?

 McDermott:  “That’s actually a very sophisticated question, and one that does not have a clear answer.  It may be, one thing you mentioned, it may be that the immune system usually recognized proteins, usually proteins associated with infections like viruses or bacteria.  So it may be, as you point, that there are certain tumors that have show these proteins to the immune system better than others.  And then the immune system can detect these proteins and say, “This is something wrong here, let’s go kill it”.  That’s one possibility, and we tried to prove that in our trial, because one of the proteins we looked at was the protein called carbonic anhydrase IX.  We thought this protein was being recognized by the immune system and that might predict for benefit, but we couldn’t prove it.  So many people suggested your theory, which was that these proteins are important, but we could not prove it in this trial.  It doesn’t mean that there aren’t others that are important, we just couldn’t confirm it.  It may also mean that there are certain aspects of the tumor, that even though it is recognized by the tumor, something is preventing it from dying under the strain of an immune attack. That has to do with how well a cancer cell dies under stress. There may be some that don’t automatically shut down when they are being surrounded, that’s part of it.   There are also other important proteins that the tumor can make to avoid detection so the opposite of what you are talking about, that barbed wire analogy.  These are proteins that the tumor can turn on, and act like barbed wire, so that when the cells are coming it, they are turned off.  So there’s a variety of different theories and more than one aspect of that.  It’s a fairly complicated story.”

 Me; Back to CA IX, the fact that you expected that more of that would lead to greater response, you found the opposite to be true?

  “No, we didn’t find the opposite to be true, we found that the folks who had CA IX protein on their tumors did well, or better than the old numbers.  Those patients responded at about the 25%, but they did as good anyone.  What was different was that the patients who didn’t have CA IX on their tumor did just as well.   So that is why I said it was bad for the research, but good for those patients.  We would have assumed, if we hadn’t done the trial, that to those patients, we might have said, ‘You don’t have CA IX on your tumor, no IL2.’ We did the trial to show that, we couldn’t.  That means that going forward,, we should include those patients getting IL2.”

 Me:  I went on IL2, and I am a complete responder, and I had a relatively low level of CA IX, so I always watch that and wonder.

 McDermott:  “You are an example of why my research career is floundering,” laughing.

 Me; Sorry, but it works for me, works for me!

 McDermott:  “I am very happy for you and for those patients on the trial.  That is why you do the research.  The CA IX story, and this was scary when I saw it, actually made it into the medical training literature.  So if you were an oncology fellow, you learned that McDermott at Beth Israel and others said CA IX was important, and that high CA IX patients should IL2 .And then when I saw the results of the trial, I thought, O my gosh, this has become gospel, and is maybe not right. You are a perfect example of it, and it means we need to do more research into the area . You are an excellent plant could not have been better.”

 Audience: Did you say that you have some non-clear cell patients on the MDX trials? 

 “Not yet. Most of them whose tumor type we knew all have been clear cell.  But in some of the future trials there are small numbers of non-clear cell patients who will be enrolled.  If there is any sense of activity, it may encourage study sponsors/drug companies to develop it in non- clear cell patients.  They will not be excluded on trials going forward.”

 Audience: So you your knowledge there is not one which is limited (to non-clear cell) for MDX 186?

 “I haven’t seen a response in that category, since most of the patients are clear cell the assumption in the field is that clear cell benefits from immunotherapy, so when you try to prove a principal, they try to collect the patients most likely to benefit, so not to put people through treatment that will not benefit.  But now that we have this proven—really not proven—but a hint of effectiveness, different types of patients are being included in the trial.  For example, the trial which includes the addition of MDX agent with Sutent allows non-clear cell patients.  Hopefully there will be more of those in the future.  The good news is there is more than one drug company developing these antibodies, and I will include those in my talk this afternoon.

We don’t do all the work at our place, but I haven’t seen a non-clear cell responder at my place.  I have seen responses with very aggressive tumors, that had sarcomatoid features, for example, but I haven’t seen one with non-clear cell.  That does not mean that it has not occurred.”

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Management of Toxicities Related to Systemic Targeted Therapy for mRCC- Hutson

Kidney Cancer Association National Patient Conference
Dr. Thomas Hutson, D.O.; Texas Oncology
April 14, 2012
Management of Toxicities Related to Systemic Therapy for Metastatic RCC

Summarized from transcript and video; edited for brevity; Many slides were text-only, so recreated to keep files sizes small. Slides recreated in bold lettering and this font to keep the files small.
To view the lecture, please follow this link; you may copy and paste it into your browser.
http://www.youtube.com/watch?v=KuJoHPA8sww&list=UUv0VRYOltlNQJLCyNMN61Nw&index=45&feature=plpp_video
 Be aware that this is a personal summary of the lectures, and that I am not a medical professional; I am a patient, highly motivated to share the information from this KCA conference.

Dr. Hutson thanks the KCA for the conference and begins:
“The “Management of Toxicities Related to Systemic Therapy for Metastatic RCC” is the bane of our existence in RCC;  Dr. Jonasch explained the drugs and their benefits earlier, but with benefits often come side effects.

Hutson 1 TT Overview Tox

About two-thirds of these side effects–the toxicities–are mild, and are managed by “supportive care”. This means using medications to ease the toxicities. About 1/3 of the toxicities are severe, and may require a dose modification, a dose holiday, stopping the medication for a few days. For most patients, when the medications are stopped, the side effects go away.  Most are not permanent.  But when toxicity becomes so severe that it affects quality of life, such that we have to withhold that medication, we may move onto another kind of therapy.

Early recognition is very important.  I cannot predict if a patient will develop a toxicity and who will not. We think about that from the research perspective, look at it from a genetic perspective.  Studies in the medical literature show that patients’ genetics can affect the patients’ toxicity to the drug.  Those studies are called pharmacogenomics or pharmacogenetics–things that make an individual patient or a group of patients more susceptible to a toxicity.

These drugs are approved and used around the world and other populations have different toxicities than patients in the US. Asian populations have more severe hematological toxicities, lowering blood counts than we see in US or western European patients.  Clearly there is something that is genetic, a so-called pharmogenomic abnormality.  Continued research in that area will help us understand that and predict who is going to have those side effects, and let us choose drugs accordingly.

Early recognition of toxicities is the key to avoiding severe toxicities and avoiding dose reductions.  When I start patients on these new therapies, I generally see them every 2-3 weeks for a few months.  Thus, we can get a handle on side effects, and have a plan, and intervene as needed.  Most side effects manifest in first couple of months of therapy, and are often chronic, ongoing. Once we identify them as potential problem for that patient, then we have a strategy. Then I see that patient less frequently, every 4-6 weeks.

I do encourage the doctors–the community oncologists—to do the same, give early aggressive management of the side effect.  But the patient or caregiver needs to pick up the phone and call the doctor or doctor’s nurse early when you have a side effect.

We must also consider long-term effects from these side effects, because patients are living longer.  With these agents, used in sequence, patients are living 3-5 times longer than they were just a few years ago. Some  patients stay on them for years.  One man in my practice has been on Sutent for eight years; there are side effects that he will live with for a long time. These therapies have only been available for 5-6 years, and we are just now learning how to utilize them and their toxicities.

hutson 2 VEGF TKI

Let’s start first with the VEGF inhibitors, and follow with the mTOR inhibitors. The VEGF inhibitors, include Avastin (bevacizumab), an antibody treatment given by IV, and the TKIs, oral drugs, Sutent (Sunitinib), Votrient (pazopanib), Nexavar (sorafenib) and Inlyta(Axitinib).  Their similar toxicities are called class effects.

Hutson 3 VEGF Class Effects
                         The effect we see in clinic and most often reported by patients is fatigue. Next are skin/hand foot sores, mouth sores, and diarrhea–daily monster diarrhea.  Cardiac concerns, the biggest being hypertension; patients’ hemorrhagic effects don’t seem very big, but epitaxis, i.e., bloody nose is very common.

What is Hand/Foot syndrome?  This is palmar plantar erthrodysesthesia, a medical term for painful palms and soles of the feet. Often with calluses form on the pressure points, even cracking. It can get very severe, so the patient is unable to use the hand or the foot, unable to walk.  One of my patients had an acute reaction with Nexavar and within three days came to me in a wheelchair. Thankfully that kind of acute reaction is relatively rare.  This type of skin toxicity manifests itself in the first 2-3 weeks of therapy, reaching a peak in the first couple of months of therapy.

How do doctors talk about this? You have all heard doctors saying, “grade 1 toxicity, grade 2 toxicity” What does that mean?

To standardize reporting, we use a common language—Common Toxicity Criteria—from the National Cancer Institute, and incorporated into clinical trials.  Every doctor can grade the toxicity of a patient in the same way.

Grade 1 would be the mildest toxicity, an eruption, and macular/popular eruption, a bumpy patch. Grade 2 would be the eruption, the bumpy, and now itching, covering less than 50% of the body surface, and Grade 3 would be that eruption, with itching and covering greater than 50% of the body surface area.

For Grades 1 and 2 we use supportive care, and topical emollients and such.  For the grade 3 toxicity, very severe, we might hold the drug, let the eruption go away, and potentially,  lower the dose.” If it continued or returned, we might change the therapy.  Same for Hand/foot Syndrome; Grade 1, minimal changes. Grade 2, more blistering, more peeling, more pain, but not really interfering with your daily activities.  Grade 3 is means it interferes with  daily activities; you can’t use your hands or feet, affecting your daily life.  Same thing; grade 1 and 2, supportive care, and at grade 3, we would be more aggressive.

There is also actually a grade 4 toxicity, which is very extreme side effects and a grade 5,  usually considered a side effect that resulted in death.

For supportive care we suggest Udderly Smooth, Bag Balm, Aveeno, non-allergenic emollients or creams; good skin hygiene, good foot hygiene, avoiding shoes with pressure points in them, pain medications, traditional pain medications.  Some patients use Solarcaine spray, which numbs the surface of the skin.

Hutson 5 SKin Care
  The next side effect, mucositis or stomatitis, those are mouth sores. We can do a mix of things–tap water or salt & soda mouthwash, that baking soda kind of mouthwash, change toothpaste, as some brands burn.
Hutson 6 VEGF Mucositis Stom

Lidocaine, such as dentists use can numb the mouth.  We don’t want the mucositis to affect the patient’s ability to maintain hydration, the ability to eat, so again, monitor it.

 

 

Grade 1; mild side effects–use all the supportive care. Grade 3, very symptomatic, can’t eat, can’t drink, very difficult, and we must consider holding the drug or lowering the dose.

 

With Hypothyroidism fatigue is the major issue and with some of our drugs, fatigue occurs in 55% -65% of patients.

Hutson 7 Fatigue Hypothy       

Fatigue has many possible causes, as it not one thing that causes fatigue in any one individual.  Patients can have multiple causes at the same time, including the disease itself, anemia, lowering of the blood count from treatment, and pain medications.

We found the association of these drugs with low thyroid early on at the Cleveland Clinic. Many of these TKIs, at some level or another can affect thyroid function. Doctors need check thyroid functions in patients, especially if they have fatigue.  This is something we can easily fix and put a patient on thyroid replacement therapy.  Levothyroxine, a thyroid replacement therapy, may be used by a 1/3 or more of patients. Thyroid problems induced by these drugs is very common.

With thyroid issues we are constantly chasing TSH. It fluctuates constantly with these agents. My patients’ TSH is going up and down on their synthroid doses, very common. The graph shown here with Sunitinib therapy, shows the fluctuations of the TSH.  If there is problem I am unable to control, I bring in a specialist, an endocrinologist.

Next is dysphagia–difficulty in swallowing–and diarrhea, which is a big side effect, so will review diarrhea.

Grade 1 diarrhea is an increase of fewer than 4 stools over baseline, i.e., normal.  In medical texts, it’s considered normal to have a bowel movement about every 36 hours. But if you are used to about 1 or 2 stools per day, and it goes up fewer than 4 more stools than what you normally have, that would be considered diarrhea.  Diarrhea is NOT based on liquid stools, but the quantity of stools. So even if you were having formed stools, if you were stooling–having more stools—several times over your normal, that is diarrhea.

Grade 2 is when your stools increase more than 4-6 stools per day, incapacitating. Patients may become dehydrated, so we think about giving IV fluids.  Grade 3 diarrhea is the very debilitating diarrhea. With the frequency of the stools, patients are becoming very dehydrated and may need lots of IV fluids, perhaps even hospitalization.

As to treatment, we try over the counter medications, Imodium or prescription meds like Lomotil, or different kinds of diets, the BRAT (bananas, rice, applesauce, toast and similar) diet, different foods. We get nutritionists and dieticians involved.  We try to bulk up the food with fiber, with Questran (check with doctor), Fibercon, different fiber products, from over the counter.  There are medications that the doctors can try, things like Octreotide or  ?????,  Sometimes we give pancreatic enzyme pills, that patients with pancreatic issues use.  But most patients have grade 1 or 2; we’ll try to control it, not eliminate it.  These patients will have diarrhea every day, but controlled with Imodium and Lomotil.Hutson 9 Hypertension

 

 Hypertension is a classic side effect, almost an on-target effect of VEGF inhibition.  It is currently being investigated to determine if hypertension can be seen as a biomarker of activity against the cancer.  That may mean that patients who develop high blood pressure while in therapy may have a better chance of response to the therapy than those who do not.

We tell other doctors not to lower the dose of the cancer drug, as that is a good sign.  Keep that going, but treat the high blood pressure.  Do that with blood pressure drugs, the kind patients are already on.

If I have a patient who that is having difficulty, and we are using 2 or 3 blood pressure drugs, I will refer him to a nephrologist, a kidney specialist, who specializes in high blood pressures issues or a cardiologist to help me.  But in general, it is very rare to find a patient who cannot be on these therapies due to blood pressure issues.  If the patient is already on blood pressure medications, he is going to have troubles down the road. We identify that before starting the therapy, be proactive. Have the patient check their blood pressure daily, keep a diary, review that, have a plan so they can stay on their therapy.

Hutson 10 Hemorrhagic Side Effects

Epitaxis–bloody nose seems to happen quite a bit, especially when seasons change.  The listed medications don’t have direct effect on the mucosal lining, but may when patients have inflammation., if they don’t make the blood is more thin. We use bedside humidifiers, Vaseline in the nose, nasal steroids and different agents to try to control it.  I’ve only had one or two patients who had a major problem.

If you are predisposed to hemorrhoids , there may be more bleeding than usual. Try the topical products here, like Preparation H.  Gingival bleeding, bleeding from the gums when you brush your teeth.  Key thing that will interest surgeons is wound complications.  If you are to have a surgical procedure, tooth extraction, or a surgical procedure that normally considered minor, you have to be concerned there could have complications with bleeding.  Sometimes we’ll have the patient hold the medication for a few days before a minor procedure.

With a major surgical procedure, the literature is very controversial about the length of time, generally a few days, but that is at the discretion of the surgeon, and their comfort level.  You would resume the medication once there was appropriate wound healing.  Usually the surgeon will visit with you a week or 10 days, and remove staples and that would be a good time to resume.

A lot of side effects and it sounds bad, but I share some hope here. Tolerance may develop with long-term use. This is information from Nexavar from the original trial.  The first, HFSR, the hand/foot syndrome is shown with the axis as cycles, 1-5, a month of therapy.  The high peak that patients seem to have in HDFS is in the first cycle and fewer as the weeks go by, they develop resistance.  Same with the skin rash; same with diarrhea, hard in the first cycle, more controlled in the end.  The fatigue is similar. So a tolerance can develop, but you have to fight through the side effects.

Now about the mTOR inhibitors.  We have Torisel or temsorilimus, a IV weekly medication and Afinitor or everolimus, the oral medication. Just as with VEGF inhibitors, these have class effects associated with both.

Hutson 12 mTOR

We see fatigue, skin rash, but no hand/foot syndrome.  It’s not that severe life/quality of life syndrome that we see with the VEGFs inhibitors.  You can get a mucositis, less severe that the VEGF inhibitors or diarrhea, but that is essentially it.  You do not get the high blood pressure issues as with the VEGF inhibitors.  Generally patients feel that the mTOR inhibitors are more tolerable, less difficult, less severe side effects than the VEGF inhibitors.

Unique about this class are hyperglycemia–raising of the blood sugar and elevation of cholesterol. If you have diabetes while taking mTORs, you may have to adjust up your diabetes medications.  If you don’t have diabetes, it can sometimes cause a drug-induced diabetes, that requires medication, and is reversible upon stopping the drug.  It is reversible side effect, but we have to plan for it.

Hyperlipidemia–elevation of cholesterol levels.  I will check cholesterol levels every two months with patients on mTOR inhibitors.  If we start to see it rise, we start them on therapy. Many of my patients are already on statins, lipid lowering medications, but it doesn’t seem much of a problem in them.  But if a patient isn’t already on, they can develop this.

Hematologic effects. The mTOR inhibitors can lower blood counts, create problems with white blood cell counts, and infections, more than VEGF inhibitors. As a class, mTOR inhibitors are not just used to treat kidney cancer.  Long term, and in Europe, they have been used as immunomodulators for transplant patients.  They change the immune cells in the body to prevent rejection of organs.  For patients with kidney cancer, we change doses, but they can create changes in the immune system and put patients to be at risk for infections, like pneumonia.  Doctors have to watch for infections when on Torisel or Afinitor.

A unique side effect to this class is interstitial pneumonitis–inflammation of the lungs. If it occurs, and causes symptoms of coughing or shortness of breath, we need to consider discontinuing therapy. More details on that.

Hutson 13 Skin

A skin rash with Torisel is usually on the torso. We use a topical crèams, emollients with Benedryl. We try to avoid using steroids, as this drug already has an immune effect and we don’t want to add to it. With a patient who has grade 2, less than 50% of the body affected in a skin rash, I sometimes get a dermatologist to help.  If the rare patient develops the grade 3, with more than 50% body surface affected, I would have to consider stopping the medication.

Hutson 13 mTOR Hyperglycemia


 Hyperglycemia has been seen with both the mTOR agents, and we need to monitor blood sugar. Sometimes that means making the patients get a blood monitor, to check their blood sugar medications at home, or start diabetes medication.

Again you can see elevations in triglycerides and cholesterol requiring patients to start on lipid-lowering medications.  Those are both reversible when you stop the medication.

Hutson  14 mTOR Infection

We talked about infection.  There is a chance of infection with the mTOR inhibitors, so we need to be on alert for that.

Hutson 15 PneumonitisSeen here are CT scans of interstitial pneumonitis: in month five there was a development of this nasty-looking infiltrate in the CT scans.  That scares everyone when we find this on a CT scan.  It could be ones, one; an atypical pneumonia, two; interstitial pneumonitis, a drug side effect, or the cancer. Sometimes, we have to refer patients to a lung specialist for a bronchoscopy to determine what it is.  In this case, it was a drug effect, not an infection, and it was not cancer.  It was the actual drug inflaming the lungs.

They stopped the drugs, they gave a little burst of steroids, it went away.  Later they rechallenged the drug, and the patient went back on the drug, without further recurrence of the interstitial pneumonitis.  If I had a patient with interstitial pneumonitis, I would find it very hard to put them back on the therapy.  I show this to demonstrate that it is a reasonable side effect to expect, and it is reversible.  It manifests itself as an x ray finding or as a cough.

Hutson 16 General Recs

The general recommendations are as shown. Call if there is any side effect which you are uncomfortable with.  It is better to call early so you can intervene on it before it becomes a problem.

END of LECTURE: Questions follow from patients and caregivers.

Patient responses; Patient suggests Rock Alum in the case of mouth sores.

4 Archway macaroon cookies, twice a day

Capcesin for foot sores

Doctor agrees that patients have much to offer help with some symptoms.

Questions re coconut oil, to be used for mouth sores; Doctor had not heard of that.

Side effects do get better, says patient, asking about taking acidodolphodus; doctor agrees that pro-biotics, yogurt, is helpful, perhaps to change gut flora.

Question re Zometa as it is used with Sutent;  Zometa has benefit in reducing skeletal related issues, and would be beneficial with all the drugs, says doctors.

As to difficult skin issues, doctors suggest the use of anti-fungals and consults with a dermatologist.

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Locally Advanced RCC /Kidney Cancer; Dr. Chris Wood; Budd-Chiari Syndrome & Nodal Disease; Part 3/4

Dr. Chris Wood; MD Anderson Cancer Center

KCA Patient Conference; April 14, 2010

Surgical Management of Locally Advanced Renal Cell Carcinoma Part 3 of 4

Budd-Chiari Syndrome & Nodal Disease

One  devastating complications of venous tumor thrombi  is  the Budd-Chiari Syndome.   The thrombus gets so big that it plugs up the vein, plugs up venous outflow from the liver. Patients present with abdominal pain, ascites, i.e., fluid in the abdomen, edema of lower extremities, enlarged liver, and their liver function tests are all abnormal.

If we take these patients to the operating room, the mortality rate is about 80%.  Because of this we no longer take these patients to the OR  Instead we will embolize the tumor, cutting off flow of the blood to the tumor.  For those patients that regress, we will take them to surgery and they do well.

It is not a very common presentation; we had six patients, two of whom were without evidence of disease after 3 years, using this approach.

NODAL DISEASE

There is a study where patients with localized RCC were randomized to either node dissection or not– to look to see if node dissection improved outcome. This trial showed that patients who had no dissection did no better than those who did not have node dissection.  Many will use this in urology community to say that patients who have kidney cancer do not need to undergo node dissection in the absence of metastatic disease.

In a more recent update on this, again, those patients who had a node dissection did no better than those with a node dissection.

But one thing about this trial that troubles me and many in the urologic community is the significant percentage of patients who had very low stage disease.  So it gets to the discussion of risk. If you study what you are doing in a low risk population where the frequency of the percent of expected adverse event is so small, you will never see a difference.  The problem with this trial is that they need to focus on more advanced stage disease to see if node dissection really makes a difference with kidney cancer.

The group at Mayo did some very elegant studies which showed us where the positive nodes are.  So now we go in and do a node dissection on a patient with locally advanced tumor, and we have a very defined area where we know the highest likelihood of metastatic disease is to occur.  If we took out all the nodes, the complications would be enormous.  We now are directed in where we go looking for nodes and remove them in that fashion.

Side 37 : The group at UCLA did a retrospective study and noted that if you did not have enlarged nodes, it did not matter if you took them out or not. Again, like the EORTC trial, but critics of this argue that it presents low stage disease.  But one of the interesting things that did notice that in the patients with positive nodes, that if you took those nodes out they did significantly better.  Indicating, even in the absence of systemic treatment, surgery could influence the biology of the tumor.

Slide 38

The group from Mayo identified features that predicted for positive nodes.  These include high nuclear grade, the presence of sarcomatoid histology, large tumors or more advanced tumors, or the presence of tumor necrosis.

38a They assessed the primary tumor when it came out of the patient, and if there were 2 or 3 of these features, the risk of having nodal disease was significantly high that they triggered a node dissection.  Now  they use this prospectively to see if this does let us give better outcomes. This may give us the ability to predict who likely has positive nodes and therefore should undergo a node dissection.

Slide 39 This was a study that was done some years back, but it intrigued me. In patients that had even met and positive nodes, for example, mets to the lungs and positive nodes.  Those patients do significantly worse in their prognosis than those without positive nodes.  This suggests some adverse biology that is associated with positive node involved. 

They also noted that if they could just dissect those nodes, again even in the presence of metastatic disease, they did significantly better than those whose nodes were left in place.

This is a study out of UCLA which shows that patients with metastatic disease do worse in the presence of positive nodes.

Slide 41a We recently looked at our experience (MDACC) with patients with metastatic RCC and positive nodes, limited to clear cell histology.  We had 55 with positive nodes compared to 322 who did not.  What we noted that those who present with positive nodes do worse than if they do not have them.

Slide 41b But you can see that if they undergo lymph node dissection, even in setting of metastatic disease, they did significantly better, almost a doubling of their survival as patients who did not.

Cytoreductive Surgery Prior to Systemic Therapy for Metastatic RCC

Slide 41c If patients do present with positive nodes, we aggressively resect them, as it significantly impacts on their ability to get treatment. So nowadays, when patients present for cytoreductive nephrectomies, if they have positive nodes, we aggressively resect them, as it significantly impacts their outcome, and their ability to go and get treatment.

 Role of Aggressive Surgical Resection in Patients with Positive Nodes in the Absence of Distant Metastases

 What about those patients that don’t have metastatic disease but just positive nodes. How do those patients do? We recently looked at our series of patients with positive nodes in the absence of distant metastases, and wanted to asses what factors predicted what affected outcome.

Slide 41d

Out of 3201 nephrectomies, we identified 2521 who did not have metastatic disease, and of those 68 had positive nodes.  Surprisingly, we found,  that in positive nodes–that the tumor has left the kidney and metastasized–and surgical patients still do pretty well.

Slide 42: There overall survival rate at five years is 37%.  You might say, that is pretty low, but that is with surgery alone.  But disease specific survival is 39% at five years.

slide44: But when disease recurs, it generally recurs early, at within the first year, but more than a third recur greater than a year out.

Slide 44a:  And when patients do recur after this surgery, they usually recur in multiple places with metastatic disease.

Slide45

We wanted to look at factors that predicted for outcomes in these patients.  So these are these are the demographics, (editor’s note; the video does not include these charts and slide, which are from the original, unedited video) the vast majority had good performance status, they had local disease, confined to the primary tumor and the overwhelming majority had clinically positive disease. This was not microscopic disease, rather big nodes you can see on CT scans.

What we noted, interestingly, in terms as predictors of overall survival those patients with papillary histology had a significantly better outcome, than those with clear cell histology. Those with only one node had a significantly better outcome than those with more than one mode.

When we looked at time to recurrence, again, papillary histology seemed to be a predictor of who would do well.  So patients with papillary histology and positive node involvement, we will aggressively resect them.

Slide 45: The multi-variate analysis  predicts for overall survival, and  papillary histology, the number of nodes positive involved,  the presence of sarcomatoid features and status all predicted outcome.

Regards of the time to recurrence, only the number of nodes involved and tumor grade were predictive of outcome in these patients.

(Slides are variations of the same information.)

Secondary Treatments

What about adjuvant therapy in these patients?  I already told you that adjuvant therapy doesn’t work. In this particular group, 5 got adjuvant ttreatment and in those 4 patients, it recurred.  The important thing is that 85% of these patients had good performance status at three months. What does this say?  It means we can do an aggressive surgical resection and patients bounce back very quickly. If they need to go on to get additional treatment, even after this very large surgery.

So these are the feature that predict outcome; papillary histology, number of nodes, sarcomatoid features and ECOG performance status.

I will continue with “Adjacent Organ Invasion” in the next part of the lecture.

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