Perioperative Systemic Therapy for Kidney Cancer: Current Data and Ongoing Trials

Kidney Cancer

 

Chicago, IL (UroToday.com) Dr. Uzzo gave the third and final talk in this excellent session highlighting systemic therapy in the management of kidney cancer. Focusing specifically on the role of perioperative systemic therapy (neoadjuvant [NAC] and adjuvant [AC]), he adeptly covered the prior literature and the future directions of this important intersection between surgery and systemic therapy. While his talk was extensive, below we will review the major highlights and key points.

Ultimately, in Dr. Uzzo’s eyes, we are all managers of health care risk. We seek to “understand, predict and prevent future health care events.” As such, from the time of diagnosis, the key steps in managing a patient are: identify risk (screening, etc), utilize risk tools to risk stratify, communicate this risk to the patient, and finally, mitigate risk with intervention.

Looking at biomarkers in the kidney cancer space, he highlights the key point that biomarkers have been few and far between for RCC. At the end of the day, commonly used biomarkers such as stage, grade, and histology still remain the standards for risk stratification. While numerous biomarkers (genetic, epigenetic, etc) have been evaluated, none have been demonstrated to be superior to stage, grade and histology. As biomarkers have failed to improve upon these factors, we also looked to different models to help stratify patients. In the localized RCC disease space, these include the UISS, MSKCC, SSIGN, and Mayo clinical models (among others) to predict recurrence, but the C-index for these tests ranged between 0.76-0.89. However, all the models shared common features that are easily identified clinically – stage, grade, tumor size, performance status, presentation, age, gender, and coagulative necrosis. Models for metastatic RCC are even less capable of predicting cancer-specific mortality (C-indices ~0.6). At this point, biomarkers and models give way to common patient and pathologic characterizations for risk stratification.

Neoadjuvant Therapy (NAT)
Dr. Uzzo provided a very nice comparison of the “Halstedian” model and “Fisheresque” model of cancer progression. Dr. Halsted, a legend in oncologic surgery, believed in stepwise progression of disease from stage 1 -> stage 2 -> stage 3 -> stage 4, which supported utilization of adjuvant therapy rather than NAT. However, Dr. Fisher was a strong proponent of the idea that a subset of patients were likely metastatic at inception, which better supported the need for NAC.

When looking at NAT, there are some key questions:

1) Does it work? (does it shrink the tumor? Can it work as a “litmus test” prior to cytoreduction? Can it control distant disease?)
2) Is it safe?
3) Are there translational signals?

In terms of tumor shrinkage, based on retrospective series and phase II trials, it results in approximately 25% tumor volume reduction, with an objective response rate (ORR) in 30-40% of patients. So, if patients are referred for that indication, that is what a medical oncologist can cite to a surgeon. However, the implications of this are heavily surgeon dependent, and as Dr. Uzzo states, it is a “function of judgment and experience” – if they feel that this will allow for partial resection vs. radical nephrectomy, or make a non-operative patient operative, then it may be worthwhile to proceed. This is difficult to quantify in clinical studies, and selection bias is an unavoidable issue. In his review of NAT to facilitate partial nephrectomy (PNx), there were <200 cases amongst 7 series.1 Similarly, there have primarily only been case reports/series demonstrating tumor thrombus reduction (25-40%), but rarely does it change the level of thrombus without a concomitant risk of toxicity.

In terms of efficacy, he reviewed a few clinical trials of neoadjuvant targeted therapies, including pazopanib.2 While many of these had some tumor size reduction, they often had high rates of patients not making it to surgery due to adverse events. Importantly though, a significant portion did not make it to surgery due to progression of extrarenal disease. As such, he emphasizes that NAT may be utilized as a litmus test for patient response. Patients progressing on NAT likely wouldn’t have benefited from surgery anyway.

No biomarkers have correlated with ORR in NAT trials.

In summary, NAT is not in the guidelines, high quality guidelines are limited, and there is no long-term data. While newer therapies (cabozantinib, immune checkpoint blockage) may change management, clinical trials are the recommendation for now.

Three clinical trials in NAT space:
CARMENA – activated in 2009, still accruing but having difficulty. Testing the importance of surgery – comparing surgery + adjuvant sunitinib vs. sunitinib alone.
SURTIME – testing sequencing (sunitinib -> surgery vs. surgery -> sunitinib). While initially expecting 440 patients, they have modified study to accrue 98 patients (study closed). In data analysis phase now.
ADAPT – SUO CTC joint effort, they have accrued 713/1133 patients in 3 years. Tests sequencing, including the use of autologous dendritic cell immunotherapy and sunitinib.

Adjuvant Therapy (AT)
Recent publications on adjuvant trials have increased interest in this treatment option. However, there are still no approved ATs for RCC. Dr. Uzzo breaks down the history of AT in RCC into three time periods: the “dark ages”, the “middle ages” and “the future.”

In the “dark ages” of AT, numerous trials were done but it combined “ineffective surgery with completely ineffective systemic therapy.” None of them showed significant benefit, though many had significant flaws.3

More recently, we have come into the “middle ages”, where we utilize “ineffective surgery with more effective systemic therapy.” As is well known, S-TRAC4 and ASSURE5, presented conflicting results regarding disease-free survival outcomes in the adjuvant setting. Dr. Uzzo did highlight the key differences in the studies (only cT3-4 disease in S-TRAC, primarily clear-cell histology in S-TRAC) that may have contributed to the discrepancy. However, even when the clear-cell subset of the ASSURE cohort was analyzed, there was no DFS benefit. Two ongoing trials for whom results are pending are PROTECT (pazopanib) and SORCE (sorafenib). The PROTECT trial investigators should be presenting their results later in the meeting.

He very nicely looked at the role of adjuvant therapy in other malignancies (breast cancer, colorectal cancer, melanoma and GIST) and found DFS benefit to be 4-11% (modest), often times with significant monthly cost. As such, he makes a good point, that adjuvant therapy touted as standard of care in other malignancies doesn’t have as much of a benefit as we often put faith in.

Adjuvant therapy is only marginally effect because of
1) Poor timing and patient selection
2) Bad biology
3) Ineffective therapies

In RCC, based on prior literature regarding growth kinetics, tumor doubling time, and presentation of metastatic disease, micrometastases typically present as visible disease between 6-11 years later. Perhaps we are not giving systemic therapy at the right time?

So, while it has not been shown to be highly effective in RCC yet, he recommends:
1) Improving timing (using CTCs and biomarkers)
2) Attacking tumor stem cells (yet to be identified)
3) Attack less promiscuous upstream targets (balance toxicity for specificity)

The future is promising. The “New” Age hopes to combine “incompletely effective surgery with potentially more effective systemic therapy.” He cites two trials, the ECOG PROSPER trial (nivolumab) and the SUO-CTC INmotion trial (atezolizumab), as upcoming studies with novel therapies that may provide new standards.

Overall, in terms of perioperative systemic therapy for RCC, there are no approved options. However, clinical trials with more effective therapies and better patient selection represent the future.

Presented By: Robert G. Uzzo, MD, FACS, Fox Chase Cancer Center, Philadelphia, PA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting – June 2 – 6, 2017 – Chicago, Illinois, USA

From https://www.urotoday.com/conference-highlights/asco-2017/asco-2017-renal-cancer/96168-asco-2017-perioperative-systemic-therapy-for-kidney-cancer-current-data-and-ongoing-trials.html?utm_source=newsletter_4518&utm_medium=email&utm_campaign=asco-2017-day-2-highlights

Giving Thanks, Day 3

Adapted from http://www.maryo.co/giving-thanks-day-3/

Today I am hugely thankful that the last major issue we had here was in 2013 when Tom had his heart attack.  That event caused me to start a whole new blog to post about our experiences.

screenshot-2016-11-05-06-30-59

Adapted from https://maryomedical.com/2013/02/08/the-beginning/

January 27, 2013 was our 40th anniversary.  DH called me and said he was leaving a conference in Washington, DC and we’d go out to brunch when he got home.

The next thing I had heard was that he was in the ER with a suspected heart attack.  I rushed to the ER and found him in his cubicle.  He’d had 3 nitroglycerine pills by then and figured he could go home.

Wrong!  They had him stay overnight at the hospital.  January 28th, they decided to send him by ambulance to Fairfax Hospital for a cardiac catheterization and possible stent.

At the end of that, the surgeon came into my waiting room and said that he needed triple bypass NOW.  Three of the arteries were 100% blocked.  They got me calmed down to see him in the OR.

He was trying to get odds of not doing this surgery and just leaving then.  Finally, I said that he would do this surgery, we weren’t going to fool with this.

I really lost it when they asked me if we had any children and I said 1 son in NYC.  They called him at work in New York and had him get there as soon as possible.  I’m sure he could hear the fear in my voice.

They wheeled DH off for surgery and I waited again.  Luckily, 2 church friends came and sat with me and our pastor arrived about 8:00PM.  Our son arrived about 8:30PM after taking the Acela and a taxi directly to the hospital.

The surgery was over about 9:00PM but when we saw Tom, he was still under anesthesia.  They kept him that way until the next morning since he was too confused when they woke him up.

Long story short (too late!) – he got out of the hospital on the 31st and I played nurse 24/7.   He couldn’t drive/go anywhere for 6 weeks, and then there were 12 weeks of cardiac rehab.

One of the things that came out or cardiac rehab was becoming friendly with 2 other couples (although one of them has since split up).  We go out to dinner every couple months…and none of the surgeons would be happy about our choices.

heart-line

A slightly different take on the events, written 3 weeks later on the same blog.

Icy Days and Mondays…*

* With apologies to Karen Carpenter!

I know I’m not supposed to “relive” events.  I have done that too often with my Cushing’s and cancer adventures and I’m told that reliving causes nearly as much stress as the original event.

So, I plan to write down my memories here and try to let them go…

It all started on Sunday, January 27, 2013 – our 40th wedding anniversary.  I picked up my mom and went to church so I could sing in the choir.  DH went to a meeting of some sort on Benghazi.

After church, I stopped off in the church office for a goodie bag that the Staff Parish Committee had left.

Dropped my mom off at her house and went home.  I put the goodie bag on the dining room table and logged onto the computer to do some work.

I got a couple text messages from DH:

Text message

I figured I’d take a nap until DH came home for that late brunch.

The next thing I hear was my phone ringing, a call from DH.  He was in the ER at Fair Oaks with a heart attack.  OMG!

I immediately leaped up and rushed out the door.  I called one of my pastors and got to the ER in record time.   When I arrived, he was in a bed, all hooked up to monitors, fluids and such.  He was awake and feeling pretty well thanks to the nitroglycerine they had given him immediately after arrival.

When we had a chance to talk, it turned out that he had been in his conference and realized his chest was getting tight.  He found the hotel’s store and bought aspirin – 3 for $11.00 which he thought was extravagant.  He bought them and took them anyway – and probably saved his life.

On the way home, he was feeling pretty good so he stopped at the mall to buy an anniversary gift.  The salesgirl in Zales didn’t know that ruby was the stone for the 40th anniversary and was kind of ribbing DH for waiting until the last minute to buy a gift.  He walked out of there, felt more tightness and headed to the ER…where he called me.

DH was feeling pretty well thanks to the nitroglycerin and aspirin plus whatever else they had in the IV and wanted to go home.  The staff said no way – he had to stay overnight so he could be monitored.

The “automatic clock” on the wall said it was Monday.  Other rooms said Sunday.  Hmmm

A trainee EMT came in to ask some questions as part of his learning process.  Every time DH mentioned the word “Benghazi”, his blood pressure spiked about 40 points or so.  That term became verboten ever after.

My pastor stopped by and we had some nice chats and prayers.

Time passed, tests were done, doctors and nurses stopped by.  Finally, DH was moved to his room upstairs.

About 9 or so I went home and found our dog huddled by the front door – I had left so quickly I hadn’t left her any lights on.  I imagine she was quite worried.

I can’t even remember what I had to eat for dinner but I really wanted something chocolate.  On a whim, I looked in that goodie bag and there was a double-sized brownie.  I think I ate that in record time and it really hit the spot.

Ice

Monday morning (for real!), I checked the weather and found that school was starting late because of icy conditions.  I put on boots and took the dog out.  It seemed to be raining – if it’s raining, it must be warm, right?  So I didn’t really pay attention (and I had other things on my mind!) and completely missed seeing the black ice.

Next thing I knew, I had fallen on one knee, my cell phone in my pocket bruised my other thigh and my left arm hurt where I’d reached out to catch myself.  Luckily, I hadn’t let go of the dog’s leash.

I ended up sitting in a puddle of icy water for a long time, figuring out how to get up.  I finally sort of crawled up the trash can that was sitting in the driveway.

The dog had an abbreviated walk, I changed my wet, cold clothes and headed to the hospital.  I was showing DH my knee and one of the staff bandaged it up for me.  I told him I hadn’t fallen at the hospital and wouldn’t sue but I guess he wanted to be sure.

(Today, Monday February 18, my knee still has a huge lump under the skin and hurts when I touch it, although I’m no longer limping,  The bruise/pain from cell phone finally went away)

The hospital staff decided DH should go to another hospital which is world renowned for its work with heart cases to have a heart catheterization and possible stent.  DH was ready to walk out to my car to drive him to Fairfax Hospital.  He wasn’t thrilled when he was strapped to a gurney and out to an ambulance instead.

I headed over in my car.  They’d changed the entrances to the hospital since the last time I was there and I couldn’t find the “Grey Entrance”.  Finally, after wandering around for a long time, I found it.

I saw DH in the prep room where they got him ready for the heart catheterization – then they rolled him away after explaining all the things that could go wrong.

I went out to the waiting room, got some coffee and a sandwich and hunkered down with my iPad.

Eventually, my beeper went off and I was called back to the room where DH had been prepped.  The surgeon was there this time.  She said that 3 arteries were nearly 100% blocked and they needed to do emergency triple bypass.  They also needed me to convince DH of this since he was figuring he could tough it out.

I started crying but she said I had to get myself together and convince him NOW.  I had to put on scrubs and off I went to the OR.  I got there, DH was on the table trying to figure out the odds if he didn’t do this surgery.  All the medical staff said that he had  a very low chance of survival without the operation.  He still wasn’t sure.  He wasn’t afraid to die.  Tough Guy, Yadda Yadda.

One of the nurses asked me if we had any kids.  I said only one, in NYC.  She said I should call him and get him here ASAP.  She even dialed the number.  I talked to DS at work and he agreed to come right away.  He was pretty scared, too.  He later revealed that he had been crying on the train ride.

I went back to the OR, told DH that DS was coming and that he was going to do the surgery like it or not.  I signed the paperwork and sent him to a very scary surgery.

It was about 4:30 by then and I needed to take the dog out again.  They said I could go home – surgery wouldn’t be over until about 8:00PM or so. Got home, took the dog, made sure that there were lights on, and headed back to the hospital.  Another pastor from my church called.  He said he’d be by the waiting room later.

Two friends from the church office texted me to say they were coming over to sit with me in the waiting room.  They got there about 6:30 and we decided food might be a good thing.  We headed out, following a variety of directions and signs and walked for a l-o-n-g time.

My knee was killing me.  We got to the cafeteria and found out that it was closed.  the 24-hour one was elsewhere.  We finally found that, got some food and my cellphone rang.  The surgeon would be coming out soon to talk to me.

We hustled back to the waiting room and the surgeon came out about 8:00 with good news.  Successful surgery!  DH wasn’t awake yet but we could see him about 9:00PM.

The pastor arrived about 8:30, then DS got there about 8:45.  Finally, they said we could see DH although he still was asleep.  My friends left, pastor and DS went in to see him in ICU, sleeping so peacefully with so many lines attached.  The pastor prayed, then left.  DS and I decided to stay to see DH awake.

About an hour later, the ICU tech said they were going to keep him asleep overnight so we went home.

Monday

Tuesday, January 29 – DS called the hospital fairly early and found that DH was still a bit agitated so they were keeping him under a bit. I took the dog out and we got ready to head back.

I got a call that he was waking up but agitated.  He kept fighting with the nurses on the day of the week.  He kept saying it was Monday, even though it was Tuesday.  Surprise, surprise.  The calendar on the wall hadn’t been changed.  It still read Monday.  No wonder that’s what he thought!

We stayed all day, though nurses, techs, doctor visits and such.  He was in ICU so was monitored very well.  DH was quite confused and repeated himself a lot.  He wasn’t quite sure what had happened.

Monday

Wednesday, January 30.  DH had been moved from ICU into a regular room and we had to follow visiting hours, even though we were family.  We could visit at 11 and had to leave at 1, then back for 6-8.  Actually, this worked out well since I was able to take my first nap since this whole ordeal began.

DH had called DS early in the morning and  said he “needed” his cell phone to make some work calls.  Luckily, DS talked him out of that, saying that he could say some wrong things, given his temporary memory issues.  Thank goodness!  I didn’t want him spending his days talking on the phone.

We got there about 10:45am and they still wouldn’t let us in due to “flu season”.  I’m not sure how we could give him the flu in those 15 minutes before official visiting hours.

I glanced at the whiteboard on the wall where the nurses’ names, doctor’s name and such were written.  Unfortunately, no one had changed this whiteboard since Monday, so that’s what it still said.  <sigh>

We visited – DH got to eat a bit and had started having lines removed.  He thought he might put his shorts on so went into the bathroom to do that.  Unfortunately, he managed to pull the IV out of his hand and bled quite a bit.  The nurse sent him back to bed and said no more of that!

A representative from the group Mended Hearts stopped by with information and a heart-shaped pillow.  They have meetings the first Saturday of the month, so we might go to some of those.

The first pastor dropped by again and we made plans for Friday to pick up DH’s car which was still at the ER.  No one else I know could get it – it’s a standard shift car.

Not much else – visiting, napping, improvements every day.

Not Monday

Finally, it’s not Monday!  Nowhere, nohow.  Just Thursday, January 31 after 4 days of Monday.  Hooray!

DS had a headache so I went to the hospital alone.  He was going to come for the nighttime visiting hours.  As it happened, DH came home this day after lots of testing, last minute X-Ray, discharge notes, complaints about the night nurse…

We got home about 5:00PM.  Yea!

Now the real work began – visiting nurses, medications, doctor visits, rehab.

Since it’s no longer Monday, this post is over 🙂

heart-line

Whew!  There was a lot more after the surgery – visiting nurses, cardiac rehab, so on and on.

I am hugely thankful for my pastors, friends, family, people who brought us dinners, all the doctors, nurses, surgeons, visiting nurses, rehab personal, Mended Hearts, ambulance folks, aspirin, nitroglycerin, insurance, Fair Oaks Hospital, Fairfax Hospital, everyone involved in any way with this escapade.

Five orange pumpkins sit in a row in front of a distressed, wooden background.

Valentine Heart

Happy Valentine's Day

From 2/14/2013 and still true today:

Today is Valentine’s Day, and not quite the way one would plan to celebrate but at least we no longer have a broken heart here.

This journey probably began a long time ago but the first we heard of it was our wedding anniversary, January 27, 2013.

Two and a half weeks later, the surgery is over, the wounds are healing, things are sort of normalizing.  I know that there’s a long way to go – more doctors, start rehab, relearn life.  But, at least we’re on the other side of the crisis now.

Lots to celebrate!

Mohs surgery

tom-earMy husband had a Mohs surgery on his ear a couple months ago and it was a really good way to get rid of ALL the cancer.

His surgeon did it in really interesting way. I had thought that they would take the first slice, then wait in the room where he was while they looked at the pathology, then take another, etc until all the cancer was gone.

Instead, they took the first slice, then back to waiting room. Next person, first slice while they were looking at the pathology, then another person, first slice…

Then a round of second slices, then thirds.

It took longer than I’d thought but it was really good talking to other family members and patients during that time.

 

 

From the Mayo Clinic

Mohs surgery is a precise surgical technique used to treat skin cancer. During Mohs surgery, thin layers of cancer-containing skin are progressively removed and examined until only cancer-free tissue remains. Mohs surgery is also known as Mohs micrographic surgery.

The goal of Mohs surgery is to remove as much of the skin cancer as possible, while doing minimal damage to surrounding healthy tissue. Mohs surgery is usually done on an outpatient basis using a local anesthetic.

Mohs surgery is an improvement to standard surgery (local excision), which involves removing the visible cancer and a small margin of surrounding healthy tissue all at once. Mohs surgery allows surgeons to verify that all cancer cells have been removed at the time of surgery. This increases the chance of a cure and reduces the need for additional treatments or additional surgery.

Are There Early Signs of Kidney Cancer?

kidney-cancerKnowing Your Risk

Kidney cancer isn’t as common as breast or lung cancer. For most people, the chance of getting kidney cancer in their lifetime is less than two percent, according to the American Cancer Society.

Your risk increases if you smoke, are obese, or have been exposed to chemicals such as asbestos and benzene. Sometimes kidney cancer can run in families. If you’re at high risk, talk to your doctor and watch out for symptoms.

Hard to Find

When someone has skin cancer, they might see an unusual growth on their skin. For example, breast cancer is often found when a woman discovers a lump in her breast. Because the kidneys are so deep inside the body, it’s harder to find kidney cancer just by looking or feeling for growths.

Searching from the Inside

Imaging tests like computed tomography (CT) or magnetic resonance imaging (MRI) can spot cancer in the kidneys. Yet these tests are costly, and they often can’t differentiate between kidney cancer and noncancerous growths.

Usually, doctors only recommend CT or MRI scans for people who are at very high risk for kidney cancer because of an inherited condition, like von Hippel-Landau disease.

Warning Signs of Kidney Cancer

Kidney cancer often doesn’t cause symptoms until the tumor has already grown. The most common symptom is blood in the urine, called hematuria. If the amount of blood is too small to be seen with the naked eye, it can be found on a urine test.

Other Symptoms

Blood in the urine is the main symptom of kidney cancer, but there are other signs too. Other symptoms include:

pain in the side or lower back

symptoms of an infection, such as fever, fatigue, and an overall sick feeling

losing weight without trying

swollen ankles

Many of these symptoms can be caused by other illnesses, like the flu or a back injury. But if these symptoms don’t go away, talk to your doctor.

What Your Doctor Might Find

During an exam, your doctor will look for other symptoms of kidney cancer that you couldn’t find on your own. They might press on your abdomen to check for a lump. Or tests might show high blood pressure or a low red blood cell count (anemia).

Kidney Cancer Tests

Many different tests can detect kidney cancer. Urine tests find traces of blood in the urine. Blood tests search for chemicals that the kidneys are supposed to remove from the body.

CT, MRI, and ultrasound scans create pictures of the kidneys and allow doctors to look for growths that may be cancerous. A biopsy removes a piece of tissue from the kidneys to be examined under a microscope for cancer.

What to Do Next

If you do have kidney cancer, your doctor will find out how advanced it is and whether it has spread to other parts of your body. This is called staging. It helps your doctor determine the right course of treatment for you.

Many different treatments are available for kidney cancer. Radiation, chemotherapy, and surgery can help stop the cancer and improve your long-term outlook.

via Are There Early Signs of Kidney Cancer? | Cancer factsheet.

A New Surgery Risk – NYTimes.com

Thousands of Americans every year develop an abnormal heart rhythm after having major surgery. These episodes have long been considered a fleeting phenomenon that is generally not a cause for concern.

But a large new study suggests that doctors should take these abnormal heart rhythms, known as atrial fibrillation, or A-fib, more seriously. It found that patients who experienced one or more episodes after surgery had a striking increase in their risk of having a future stroke. The findings are likely to encourage doctors to potentially monitor and in some cases treat the patients who experience them.

“This is telling us that once you see atrial fibrillation in the hospital, that’s a marker of potential trouble to come,” said Dr. Donald Easton, a clinical professor of neurology at the University of California, San Francisco medical school.

Read more at  A New Surgery Risk – NYTimes.com.

Minimally Invasive Multivessel CABG

This is a video showing Coronary Artery Bypass Grafting being done through left 4th intercostal space by a 6-7cm incision.

We are routinely doing Coronary Artery Bypass Grafting, single vessel or multivessel through left 4th or 5th Intercostal Space depending on position of apex of heart and the target arteries on routine chest x-ray and coronary angiogram. We are using skeletonised LIMA and Free Radial Artery to construct a ‘Y’ and then pick all the vessels to be grafted sequentially. Single Lung ventilation using an endobronchial tube is essential.

Team Includes Dr.Kshitij Dubey (Chief Cardiac Surgeon), Dr. Vikas Gupta (Chief Cardiac Anaesthetist), Dr. Krishnpal Singh (Anaesthetist) Mr.M.V.Krishna Mohan (Sr.Clinical Perfusionist), Rajshree Hospital & Research Centre, Indore, Madhya Pradesh.