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

Menopause sometimes requires a survival guide

Menopause has gotten a bad rap. Women in their 40s and 50s who have any symptoms – from moodiness to insomnia and headaches – may believe that it’s a normal part of aging and there’s not much they can do about it.

Fluctuating hormones caused by the normal decline of ovarian function can trigger the typical symptoms associated with menopause. One approach is to give the body a drug that mimics ovarian function, such as estrogen or hormone replacement therapy. This was a common treatment, until multiple studies showed increased risk of urinary incontinence, stroke, dementia and breast cancer from using menopausal hormone therapy.

Fortunately, there is another approach to improving the body’s ability to adjust to hormone fluctuations that doesn’t increase the risk of breast cancer and dementia. This approach looks at the other organ systems that are involved in addition to the ovaries. For instance, hot flashes will be greatly exaggerated in a woman who has blood-sugar problems – even if those don’t show up on a standard blood test.

BIOIDENTICAL HORMONES

Some women use bioidentical hormones instead. While they appear to have fewer immediate side effects, there is no evidence that they have fewer long-term risks.

At a recent functional medicine conference I attended, there were several discussions on how to address hormone “saturation” – the experience many women have after being on bioidentical hormones for several years and then having a return of their previous symptoms. We’re learning that underlying imbalances in gut function, adrenal hormones and blood sugar can have a major effect on a woman’s experience of her perimenopausal years.

IT’S NOT JUST THE OVARIES

Technically, menopause occurs when a woman hasn’t had a period for 12 consecutive months. The symptoms that can occur for years before that are due to the ovaries becoming less predictable in their hormone production. This means that estrogen levels can spike and fall like a roller coaster.

Unfortunately, once a woman knows that her hormones are fluctuating, she is likely to explain away all her symptoms as perimenopausal. But ovaries are not the only glands affected by hormone changes. The pancreas, thyroid and adrenal glands play key roles in determining how easy or difficult the perimenopausal years will be.

The most common, end-stage effect of pancreas dysfunction is diabetes. But long before the body reaches a disease state, there are more subtle effects. For instance, a woman with low blood sugar or insulin resistance will experience more severe hot flashes than a woman with normal blood-sugar regulation.

Following are common symptoms associated with perimenopause and factors that can determine the severity of those symptoms.

• Heavy or frequent periods. These can be worsened by blood-sugar and thyroid imbalances that don’t show up on routine blood work. Checking free and total levels of T3 and T4 as well as thyroid antibodies can be helpful.

• Hot flashes or low libido. Underlying adrenal stress can result in cortisol levels that are too high or too low, or reduced DHEA (precursor to several hormones). Cortisol levels are best tested with multiple saliva samples over a 24-hour period.

• Insomnia. With or without hot flashes, insomnia is often due to chronic stress, which causes the adrenals to produce excess cortisol.

• Mood changes and brain fog. Moods can be affected by the stress hormone cortisol as well as imbalanced neurotransmitters. Neurotransmitters such as serotonin are made primarily in the gut and can be evaluated with a urine test. Low levels of serotonin can also increase overall pain levels.

• Hair loss and weight gain. There may be underlying thyroid stress that doesn’t show up on routine blood work but requires a more detailed look at free and total levels of T3 and T4 and thyroid antibodies.

Once these underlying issues are identified, they can be addressed through food choices, lifestyle factors and specific supplements.

Marina Rose, D.C., is a functional medicine practitioner, certified clinical nutritionist and chiropractor with an office at 4546 El Camino Real in Los Altos. For more information,  visit DrMarinaRose.com.

From http://www.losaltosonline.com/special-sections2/sections/your-health/53300-

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!

Menopausal Hormone Therapy

PS-main-logo

Menopausal Hormone Therapy and Health Outcomes During the Intervention and Extended Poststopping Phases of the Women’s Health Initiative Randomized Trials

JAMA, 10/02/2013  Evidence Based Medicine  Clinical Article

Manson JE et al. – Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. To report a comprehensive, integrated overview of findings from the 2 Women’s Health Initiative (WHI) hormone therapy trials with extended postintervention follow–up. Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow–up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women.

Methods

  • A total of 27 347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers.
  • Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102).
  • Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429).
  • The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow–up until September 30, 2010.
  • Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively.
  • A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death.

Results

  • During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95–1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01–1.53).
  • Other risks included increased stroke, pulmonary embolism, dementia (in women aged >=65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms.
  • Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow–up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11–1.48]).
  • The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78–1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61–1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65–0.97).
  • Results for other outcomes were similar to CEE plus MPA.
  • Neither regimen affected all–cause mortality.
  • For CEE alone, younger women (aged 50–59 years) had more favorable results for all–cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age).
  • Absolute risks of adverse events (measured by the global index) per 10 000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50–59 years to 38 for ages of 70–79 years; for women taking CEE alone, from 19 fewer cases for ages of 50–59 years to 51 excess cases for ages of 70–79 years.
  • Quality–of–life outcomes had mixed results in both trials.

From http://www.mdlinx.com/internal-medicine/newsl-article.cfm/4870253/ZZ4747461521296427210947/?news_id=466&newsdt=100213&utm_source=Newsletter&utm_medium=DailyNL&utm_content=General-Article&utm_campaign=Article-Section