Category Archives: Surgery

Clinical Trial for NEWLY DIAGNOSED–Surgery Now or Later with an Immune Therapy Option

Kidney cancer patients are stunned by their diagnosis, anxious to make a treatment decision, and  simply not know what to expect.  If you are struggling with the issue of surgery to remove the tumor/kidney or to start with a med, you need to read this.  Deb Maskens, Kidney Cancer Patient and Patient Advocate, our guest writer is a valued member of our disease community and currently serves on the Renal Task Force for the National Cancer Institute.  A series of links below will also be helpful.  (My extra comments will be in italics, like this. )Welcome aboard, Deb! 

Clinical Trial Opportunity for Newly Diagnosed (Non Metastatic) Kidney Cancer

As a community of kidney cancer patients, we  hear from newly diagnosed patients  looking for treatment options. This is written for those patients, and for patient advocates who help patients navigate through their treatment decisions.

The challenge: this clinical trial is available at many locations across the U.S. and Canada, but patients must ask about it BEFORE they have a nephrectomy. Their own doctors may be unaware of the trial and how to work with the trial centres.  In many places, patients get booked for surgery prior to learning about this option.  That would be too late for a trial like this–it gives a drug therapy before the surgery for a brief period.  (In one of the t wo arms, there is medication before the surgery.)

Why Might Patients Consider this Trial?

For years, the standard of care for early stage kidney cancer has been to remove the tumour surgically, sometimes with the entire kidney–either a partial or full nephrectomy. That was the end of treatment and the beginning of surveillance to watch for any signs of recurrence.  (And early stage tumors can be quite large–up to 7cm or about 2 3/4″.)

Now we hope to prevent a recurrence of disease. Since advanced or metastatic kidney cancer is still incurable for the vast majority of patients, this is a worthy goal. With preventive or ‘adjuvant’ treatments, maybe we can stop the disease before it gets to the lungs, liver, bones — to those places where it begins to threaten our lives.  Other cancers use this approach and offer patients a real chance to avoid recurrence.

Adjuvant – and Perhaps One Step Better to Neo-Adjuvant

We’ve seen trials for “Adjuvant” (or preventative) therapy which hope to prevent recurrence (treatments given immediately after nephrectomy). But one trial goes one step better – it’s for “Neo-Adjuvant” (before nephrectomy) as well as Adjuvant (after).

Patients may want to rush to surgery to “get it out”. In reality, those tumours have generally been  growing slowly, undetected for many years. Kidney cancer surgery is rarely an emergency. There is usually time for a second opinion and to check out any newer approaches.

Here’s the thought: given that the tumour cells have gone undetected and tolerated by the immune system for so long, can put those millions of cells to work and make them “show their calling cards” to our immune system before we take them out?

Combining Neo-Adjuvant and Adjuvant Treatment – PROSPER-RCC

The Phase 3 clinical trial called PROSPER-RCC (NCT03055013) is  for patients whose tumors are 7cm (2 ¾”) and larger in size, but not spread beyond the kidney area.  These patients are at greater risk of spread of the cancer than those with Stage I or with smaller tumors.

Based on earlier studies, nivolumab (Optivo) is now approved for advanced kidney cancer. This is a trial to test whether there is a benefit when nivolumab is given immediately before and after a nephrectomy when tumor cells might have spread outside the kidney but are too small (microscopic) to see on scans.  (Typically a patient without spread of disease would not be treated, but monitored.)

The Rationale for PROSPER-RCC: Why It Might Be Helpful

Here’s what I’ve learned:

  • Checkpoint inhibitor treatments with PD-1 blocking drugs like nivolumab seem to work best when the immune system may be being turned off by this cellular growth pathway. Cancer is deceptively clever and some tumours can express a protein, PD-L1. This protein can turn off our immune cell responses that recognize and fight the cancer.  There was a hint of this  with some positive data that indicates that these drugs work best in patients whose tumors were “PD-L1 positive”.  (PD means Programmed Death and PD-L Programmed Death Ligand or connector.  Death to the cells, and the signalling loop that hinders the immune response.)
  • In theory, when the kidney tumour is in place, there are millions of cancer cells. All of those tumour cells send off multiple negative signals to the immune system to stop it from working. However, if a checkpoint inhibitor was used and stopped those blocking signals, the immune system would have a big wake-up call – e.g., lots of targets with which to build an army of T cells. In theory, these newly educated T cells would later turn into memory cells. (If the body can maintain these memory cells, they would continue to fight any return of disease.)This is much like what happens when we are exposed to certain bacteria or viruses. Once we get exposed to the bug, we don’t usually get it again. Our immune cells have learned (“immunity”) how to kill it more quickly the next time before it turns into a full blown cold. Similarly, if these anti-RCC immune cells ever see one of these tumor cells anywhere in our bodies again, they would know to attack and kill them even if there is no drug in the patient and has not been for some time.
  • Surgery is still the main treatment to control early stage kidney cancer. But it will also remove the majority of targets (PD-L1) that the checkpoint drug uses to rev up the immune system. Giving the checkpoint inhibitor before surgery may maximize/optimize the drug’s ability to wake up the immune system and build that T cell army.
  • So the surgery is important. But let’s assume a few cells might be still circulating and have gone undetected for some time. They could still show up later on a scan as an enlarged lymph node or spot somewhere. A boost of the same checkpoint inhibitor right after the surgery could then be used to remind the immune system to continue to look for those cells and kill/eliminate them when they are small. In theory, the immune system will remember what the past “trouble” was: “Hey, haven’t I seen you before?”

From what I understand, this theory worked well in mice. The checkpoint inhibitors worked better if the primary tumour was there to help provide “a target” to activate the immune system first before the tumor was removed.  While we’re not mice, this  makes sense, no?

Trial Design: What Really Happens to the Patient in the Trial

PROSPER-RCC will place patients randomly into two groups:

  • Group One gets two infusions of nivolumab before surgery (at about 28 days and 14 days before surgery). Following that nephrectomy, the patient will receive more infusions of nivolumab. This is for 9 months post-surgery altogether, with 12 more doses.
  • Group Two gets the usual standard of care: upfront nephrectomy, partial or radical nephrectomy, and will be followed by close observation at an expert centre.
  • Two arms/groups:  BLUE arm with surgery  and monitoring by the trial team, the standard of care; the RED arm with  medication before to surgery, followed by more after the surgery.

It is important to note that no patient on this trial receives any intravenous placebo/inactive treatment. Every patient is treated.  Each patient will have either the experimental treatment or the standard of care.  All are under close observation at the trial centre. This trial has been designed and discussed with patient advocates and is supported by the NCI.

For More Information

Patient-friendly explanation herehttp://www.10forio.info/clinical-trials/prosper-rcc

For contact information at over 100 trial sites, dig a bit in the site below:

https://clinicaltrials.gov/ct2/show/NCT03055013

or call the office of the Principal Investigator, Dr. Lauren Harshman, at: 617-632-2429

Deb’s Disclaimer:

As a patient and advocate for kidney cancer patients, I have been delving into the world of clinical trials and trying to understand as much as I can. I’m not a scientist, but I am a patient with this disease, so I bring that lens, along with some abilities to translate science into understandable terms. As a volunteer, I have no financial interest in this trial or any specific medications. @DebMaskensKCC; dmaskens@rogers.com

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Filed under Clinical Trials, FDA Medications, Immune Therapies Old & New, Making a Plan, New Trials, Newly Diagnosed, Patient Resources, Surgery, Therapies, Uncategorized

New “NEWS!” for Non-Clear Cell re NIVO or NOT? Limited data or a light along the way?

With the headline, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”, the article should be welcome to all of those in the  in the non clear cell RCC world.  Clear cell  is the most common, the garden variety of renal cell carcinoma.  This is welcome news, as the non clear cell patients get very little attention from the research world. Though the patient with nccRCC might interpret this as, “Good news! Now that they know what to do for me!” , it is just not the case.  Rarely is the news all that good or all that simple.

Let’s back up here and lay the groundwork.  Clear cellRCC, or ccRCC is the most common of about 10 RCCs.  They all land in the kidney, but can vary widely. ccRCC may be about 65% to 85% of the cases of kidney cancer,  with the rarer non-ccRCCs making up the rest.  Maybe 15-35% of the RCCs are considered rare, with the most common Papillary Type I, Papillary Type II, chromophobe, clear cell papillary, collecting duct/Bellini’s, medullary,  translocational (not to be confused with transitional, etc, etc.) and to make it still more confusing, unclassified RCC. But when the most common is described as either 65% of the whole or 85% percent, you have to question if there is clarity in that category!

Clinical trials for RCC have usually only included patients who had clear cell. The reasons are simple; it is the biggest group, the patients can be more readily found, and that is the largest group in need of the medications.  But the patients with nccRCC are really also terribly underserved.    Back in the day, none of us had many options beyond surgery, so little distinction was made.  The prognosis was grim all around, once the cancer had spread.

But the new world of precision medicine, in its name alone, reminds us that the meds need to be developed more precisely, that they be given to the right patients at the right time.  The general crap shoot or “wild-ass guessing”, as a friend says, still remains.  The latest (not necessarily greatest) group of meds are the newish immune therapies.  You have seen their ads, no doubt.

One of those is Opdivo or nivolumab, its research name.  It tries to unblock some of the inhibiting mechanisms that prevent the immune system from doing its job, but it has been tested in trials only with clear cell patients.  BUT,  that does not mean that only clear cell patients are being prescribed the meds–this, thanks to the slightly wild west of the US medical system, that can truly go beyond the FDA approved medication guidelines.

This study, which will be formally presented at ASCO in June, 2017 was announced with the headline above, “Nivolumab Shows a Substantial Objective Response Rate in Refractory Non-Clear-Cell Renal Cell Carcinoma”.  The researchers are NOT in charge of the headlines, so we must dig deeper and see what this study really means to the patients with nccRCC

I tried to sort out what it means–or does not mean. My quick review is that it does not give a great deal of clarity to the majority of those nccRCC patients. A more complete report may improve upon this.  Based on this link, I offer the following:

http://www.practiceupdate.com/news/16132/67/10?elsca1=

“I am always concerned that these new study reports are characterized carefully. They are always more complex and incomplete than I would like. A patient in a forum says this tells of  ‘good’ responses, and especially so for the non clear cell group, but s does ‘good’ really mean generally a benefit to those rarer nccRCCs? Until a fuller report emerges, I can only note the following:

There were 23 patients, from three centers, with a median age of 59. Surprisingly 30% were African -American. This may tell us that there are more African-Americans with the rarer non-clear cell RCCs, or  could reflect the local population of the three centers.  Only 23 patients and with a mix of diseases will never meet the statistically critical requirements to reach the level of excellent evidence–but it may be all we have at this point.

All 23 had non-clear cell, but nearly half had ‘unclassified’ RCC, quite a high rate.  Usually that is considered to represent between 1 to 4% of renal tumors. Most of the rest were papillary, but they generally make up the largest percentage of nccRCCs. No distinction is made here between Papillary Type I or Type II, which are really quite different diseases. Papillary Type I and II are the most common of the uncommon, non clear cell RCCs, and are readily distinguished from each other.  This would be valuable info, and wonder if this was noted in the fuller report. 

Only 3 of 4 patients had nephrectomies before the trial treatment. Were 1 of 4 patients too sick to be given the standard of care of surgery or were their doctors unaware of that? How does this affect the study, and were the no nephrectomy patients from one center or with one subtype?   We do not know the reason for this high rate of no surgery, and at a time in which it is clear that the removal of the tumor is a great benefit to the patient, metastatic or not.

Two-thirds had metastatic disease at the time of diagnosis. Of the total 23, 74% had a prior treatment, mostly Sutent or Votrient. Of these patients with prior treatments, 26% had TWO such treatments.  Thus these patients had already received treatments that were not directly approved for their subtypes.  This is not too rare in the US, where we have greater leeway from our prescribing doctor than do patients elsewhere.  But how does this fit in with the relatively low rate of nephrectomies?

This report does not say how quickly they were treated, i.e., how long from initial diagnosis until treatment with Nivolumab?A patient with Papillary Type II found to have no metastatic disease at the time of diagnosis, but who received a nephrectomy, was monitored for a year or so, then went on one or more systemic therapy is quite different from the patient with an unclassified RCC,  metastatic at the time of diagnosis, not given a nephrectomy, though treated quickly with Nivolumab.  What can be learned when there are such wide variations in just 23 patients that would be helpful to the Papillary Type 1 patient?

The follow up period was a median of 6.5 months, which seems very short, especially when the median Progression Free Survival of the responders was 4.2 months. The median OS is not given. That certainly may reflect an ongoing study situation, or a failure to provide a longer period of follow up.

As to objective response, 6 of  the 21 evaluable patients (29%) had a Partial Response, which would likely be a 30% reduction in metastases. Another 4(19%) had Stable Disease. Two of the 23 patients died, but not from the treatment. (Assume that had to be due to the disease, but certainly indicates that for nearly 10% of the patients, this was not at all effective.)

When the final analysis was done, nine patients were still receiving Nivo. Newly recruited patients might still be in treatment at that time, but those recruited earlier may have gone out of the trial at the same time.  It is important to not that Nivolumab treatments were stopped in three patients due to intolerance, and six more had postponed treatment, i.e., 9 of the 23.

Certainly we need to find meds which create responses for nccRCC patients. However,  I am concerned we draw any certain conclusions from this study.  Indeed, it is “good” to know that the treatment was tolerable for the majority of the participants, but not so good to read that 6 of the 21 patients had to postpone treatment, and three were removed from treatment due to intolerable/toxic side effects.  We also do not know which subtypes seem to have shown responses, which would have been qutie easy to report.  Did the group with Papillary Type II do generally better that the majority “unclassified” group?  No answer from this stury report. And in the back of my head, I keep wondering why in the world there were so many unclassified patients in this small study?  Was there a standard pathology review, or could these patients been misdiagnosed by one pathologist. Typically there is a single pathologist which can standardize the reporting.  Were all these patients properly diagnosed?

Just wishing there were greater clarity and hoping to get a fuller report, post ASCO.

Without a doubt, the ‘good’ that comes from this sort of report begins with the recognition that the nccRCC group is underserved by the research community> They probably have the poorest outcomes, rarely have a clear diagnosis, and must wait for the ever popular “further research is warranted.”  But all must be aware that these very small observational studies must be reviewed very carefully for what they show or do not show.  Again, one to watch at ASCO, but not enough to make a major change in treatment for any one with a non clear cell RCC.

PS.  Does your doctor know that there are at least four subtypes of clear cell–the big ‘common’ group–which have clearly different survival patterns?  Thought so.

 

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Filed under Basics, Clinical Trials, Immune Therapies Old & New, Rarer RCC Cancers, Surgery, Therapies, Uncategorized

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

 

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Filed under Guidelines, Newly Diagnosed, Surgery

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

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

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

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

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

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

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

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

What else should trigger a genetic testing?

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

Early onset of kidney cancer is 46 years or less.

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

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

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

Personal or family history of kidney cancer syndromes.

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

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

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

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

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

http://www.cancer.gov/cancertopics/causes-prevention/genetics/genetic-testing-fact-sheet

Birt-Hogg-Dubé syndrome:
http://www.bhdsyndrome.org/for-families/what-is-bhd/

Other syndromes causing kidney cancer:
http://www.bhdsyndrome.org/for-families/kidney/other-causes-of-hereditary-kidney-cancer/

 

 

 

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

Radiation for RCC? What Really Works?

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

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

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

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

Forget shaped. Conformal small fields–yes.

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

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

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

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

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

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

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

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

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

 

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Immunotherapy and PD1: Back to the Future of 1992

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

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

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

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Immunotherapy Part 2: Is There Any Hope?

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

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

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

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

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

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

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

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

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

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

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

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

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

 

 

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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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