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

May is Melanoma Awareness Month

 

I’ve posted about our family’s experiences with melanoma before.  We were lucky and caught it in time but a good family friend didn’t.

May is designated as National Melanoma Month.   Included in that designation is National Melanoma Monday, which is the first Monday in May.  The American Academy of Dermatology has set aside this day to raise awareness about skin cancer.

Melanoma is a type of skin cancer, and it is the deadliest of skin cancers.

There will be many events focused on skin health, sun safety, tanning prevention, and skin cancer screenings and resources.

All are asked to join the American Academy of Dermatology in wearing orange and encouraging others to wear orange for skin cancer awareness.

Know the warning signs and check with your doctor if any of them appear.

Early signs of melanoma are changes to the shape or color of existing moles or, in the case of nodular melanoma, the appearance of a new lump anywhere on the skin. At later stages, the mole may itch, ulcerate or bleed. Early signs of melanoma are summarized by the mnemonic “ABCDE”:

  • Asymmetry
  • Borders (irregular with edges and corners)
  • Color (variegated)
  • Diameter (greater than 6 mm (0.24 in), about the size of a pencil eraser)
  • Evolving over time

These classifications do not, however, apply to the most dangerous form of melanoma, nodular melanoma, which has its own classifications:

  • Elevated above the skin surface
  • Firm to the touch
  • Growing

Metastatic melanoma may cause nonspecific paraneoplastic symptoms, including loss of appetite, nausea, vomiting and fatigue. Metastasis of early melanoma is possible, but relatively rare: less than a fifth of melanomas diagnosed early become metastatic. Brain metastases are particularly common in patients with metastatic melanoma. It can also spread to the liver, bones, abdomen or distant lymph nodes.

 

Melanoma Monday

melanoma

 

May is designated as National Melanoma Month.   Included in that designation is National Melanoma Monday, which is the first Monday in May.  The American Academy of Dermatology has set aside this day to raise awareness about skin cancer.

Melanoma is a type of skin cancer, and it is the deadliest of skin cancers.

There will be many events focused on skin health, sun safety, tanning prevention, and skin cancer screenings and resources.

All are asked to join the American Academy of Dermatology in wearing orange and encouraging others to wear orange for skin cancer awareness.

HOW TO OBSERVE

The 2016 theme is Looking Good in 2016 so use #LookingGoodin2016 or #MelanomaMonday to post on social media.

HISTORY

Founded by the American Academy of Dermatology, National Melanoma Monday has been raising awareness since at least 1984.  For more information on prevention and screening visit www.melanomamonday.org.

Read more at http://www.nationaldaycalendar.com/national-melanoma-monday-first-monday-in-may/

 

World Cancer Day 2016

Other Stuff, Part 2: Kidney Cancer

Until I saw it on Facebook, I didn’t know that today was World Cancer Day.  Over the years, our family has dealt with several types of cancer and I have friends that have had cancers of their own.  I think that most every family has been touched by cancer in some way.

In my family:

Colon cancer

  • My dad had it twice and died after his second surgery
  • My aunt had it twice and died after her second surgery.  She was lucky – she never had any symptoms except looking like she was pregnant.
  • My mom had it twice and she’s still alive at 93.  Hooray!  It can be beat with the right attitude.

Kidney Cancer

According to my “risk factors”, I “should” have had colon cancer because both parents and an aunt had it twice each.  Of course, there’s no guarantee that I won’t get that, too.

And the risk factors for kidney cancer aka renal cell carcinoma?  The majority of kidney cancers are renal cell carcinomas.

Risk factors for renal cell carcinoma include:

  • Age. Your risk of renal cell carcinoma increases as you age. Renal cell carcinoma occurs most commonly in people 60 and older.

I was younger than this.

  • Sex. Men are more likely to develop renal cell carcinoma than women are.

I am female

  • Smoking. Smokers have a greater risk of renal cell carcinoma than nonsmokers do. The risk increases the longer you smoke and decreases after you quit.

Not me!

  • Obesity. People who are obese have a higher risk of renal cell carcinoma than do people who are considered average weight.

A Cushing’s gift

  • High blood pressure (hypertension). High blood pressure increases your risk of renal cell carcinoma, but it isn’t clear why. Some research in animals has linked high blood pressure medications to an increased risk of kidney cancer, but studies in people have had conflicting results.

Never had this until the kidney cancer.  It went away immediately post-op.

  • Chemicals in your workplace. Workers who are exposed to certain chemicals on the job may have a higher risk of renal cell carcinoma. People who work with chemicals such as asbestos, cadmium and trichloroethylene may have an increased risk of kidney cancer.

What?  Me work?.

  • Treatment for kidney failure. People who receive long-term dialysis to treat chronic kidney failure have a greater risk of developing kidney cancer. People who have a kidney transplant and receive immunosuppressant drugs also are more likely to develop kidney cancer.

Nope.  Some sites also list polycystic  kidney disease.  I don’t have that but half my husband’s family does.  Hmmm – wonder if that’s contagious

  • Von Hippel-Lindau disease. People with this inherited disorder are likely to develop several kinds of tumors, including, in some cases, renal cell carcinoma.

I’ve wondered about this but, you know, it’s too “rare”.

  • Hereditary papillary renal cell carcinoma. Having this inherited condition makes it more likely you’ll develop one or more renal cell carcinomas.

Not that I know of. 

Pretty close to zero on the risk factors. No signs, no symptoms. I was diagnosed in the ER of my local hospital in 2006.

Skin Cancer

  • My husband has had a variety of melanomas and other skin cancers removed

Breast Cancer

  • Sister-in-Law

Among my friends, there have been many cancers – breast cancers, lung cancers (including people who have never smoked), multiple myelomas,  neuroendocrine cancers (this one is supposed to be really rare.  I have 3 friends with this.), probably some I don’t know about yet – and maybe it is unknown to the person.

Some ideas how to protect yourself and others from cancer.  It could save your life!

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.

Melanoma skin cancer guidelines for NHS updated – BBC News

New guidelines for diagnosing and treating melanoma skin cancers have been issued to the NHS in England.

The National Institute for Health and Care Excellence (NICE) hopes they will end a wide variation in the diagnosis and treatment of the disease.

They include advice on diagnosing how far the cancer has progressed, identifying the best treatment, and improvements to follow-up care.

Melanoma is a form of skin cancer that claims more lives than any other.

In 2012, the UK saw more than 2,000 deaths from melanoma and the number of melanoma cases is growing faster than any of the 10 most common cancers.

Experts believe this is largely down to the boom in foreign holidays over the past 40 years and, more recently, a big increase in the use of sunbeds.

Safe sun

Prof Mark Baker, from NICE, said everyone wants to enjoy the sun, but there are safe ways to do so.

“Using a sunscreen with a high SPF, spending time in the shade between 11:00 and 15:00, ensuring you don’t burn, and covering up with a hat, T-shirt and sunglasses.

“But overexposure to ultraviolent light from the sun can have very serious repercussions.

“Melanoma causes more deaths than all other skin cancers combined. Its incidence is rising at a worrying rate, faster than any other cancer.

“This new guideline addresses areas where there is uncertainty or variation in practice, and will help clinicians to provide the very best care for people with suspected or diagnosed melanoma, wherever they live.”

Experts warn that even though more people are now aware of the dangers of too much sun, it will be a generation or so before the number of melanoma deaths starts to fall.

via Melanoma skin cancer guidelines for NHS updated – BBC News.

Skin Cancer

biopsy

 

 

We have a new melanoma in the family, so I’ll be posting a bit about that for a while.

I just had a shave biopsy above my eyebrow last Tuesday and I’ll have 3 punch biopsies on my legs next Tuesday.  Results to follow!

For the non-squeamish: