Category Archives: Other Cancers

Do Heartburn Medications Cause Kidney Disease? Dementia?

Diana Zuckerman, PhD and Farzana Akkas, MSc,

In 2016, research was published indicating that people who take popular heartburn medications are more likely to develop serious kidney disease.[1] In 2023, research was published showing that people prescribed these popular medications are more likely to develop dementia. If you take any of these drugs, how worried should you be? And are there safer medications that work just as well?

Prilosec, Nexium Prevacid, Kapidex, Aciphex and Protonix are all a type of drugs called Proton Pump Inhibitors (PPI). There are several other drugs of this type as well.  They are all used to treat heartburn and acid reflux. In a 2016 study lead by Dr. Morgan Grams of Johns Hopkins University, people who use PPI are more likely to develop chronic kidney disease compared to those who take other types of heartburn medication.  The higher the dose or the more often they take these drugs, the more likely they are to develop kidney disease.[1] In the first of several expected settlements, in October 2023 AstraZeneca agreed to pay $425 million to settle about 11,000 lawsuits in the United States that claimed that Nexium and Prilosec caused chronic kidney disease. AstraZeneca did not admit wrongdoing under the settlement, part of broader litigation against makers of PPI that involve several major pharmaceutical companies.

Even more important, the researchers found that most of the 15 million Americans who were prescribed a PPI don’t really need them.  One in four of long-term users can stop taking them without suffering from more heartburn or acid reflux.[1]

Since the research on dementia is more recent, let’s focus on that first. The 2023 study of more than 5,000 people ages 45 and older who did not have dementia at the start of the study concluded that those who take PPI for 4.5 years or longer are more likely to develop dementia.[2] The study compared more than 4,000 people who did not take the drugs to 1,490 adults who took PPI for up to 2.8 years, between 2.8 to 4.4 years, or for more than 4.4 years. During the 30 years of the study, 585 people (10%) developed dementia. Of the people who did not take the drugs, 425 people developed dementia, which equals 1.9% per year. Of the 497 people who took the drugs for more than 4.4 years, 58 people developed dementia, which equals 2.4% per year. THESE numbers seem small but they add up over time (for example, 38 compared to 48 over 20 years). Researchers did not find a SIGNIFICANT increase in dementia for people who took the drugs for fewer than 4.4 years. This study does not prove that PPI causes dementia but it shows an association which could be caused by the drugs or could be caused by an unknown behavior or medical condition that causes both heartburn and dementia. More research is needed to determine whether long-term PPI use actually causes dementia.

The evidence regarding PPIs and kidney disease is more conclusive. Even before the 2016 study, research had shown that people who take these drugs are more likely to have painful kidney problems such as acute kidney injury and acute interstitial nephritis.[3, 4, 5, 6, 7] The 2016 study is important because the patients taking a PPI developed chronic kidney disease, which is more serious.  It means that their kidneys can no longer filter blood effectively, which can cause kidney failure. Those patients will need dialysis.

Do PPI cause these health problems or does overeating cause these problems? To address this question, the researchers compared results of PPI users to people taking a different type of heartburn medication called H2 blocker users (such as Pepcid, Tagamet and Zantac). After statistically controlling for heath factors such as obesity and hypertension, they found that people who used a PPI were still more likely to develop chronic kidney disease when compared to people using H2 blockers.  And, those who took the PPI medication twice a day were more likely to develop chronic kidney disease than those who took it once a day.

Another study, based on more than 190,000 veterans taking heartburn medication came to a similar conclusion. Regardless of their age and health, the PPI users in that study also were more likely to develop chronic kidney disease than the veterans taking H2 blockers.[8]

H2 blockers like Pepcid, Tagamet or Zantac are less expensive and seem to be safer than the PPI medications.  Many of them are available without a prescription.  And of course, a major cause of heartburn and acid reflux is our health habits. Maintaining a healthy weight and quitting smoking helps reduce the chances of heartburn or acid reflux.  If that doesn’t work, some people find it helpful to avoid spicy or greasy food, chocolate, mint, and coffee until the symptoms go away.[9]

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

  1. Lazarus, B., Chen, Y., Wilson, F. P., Sang, Y., Chang, A. R., Coresh, J., & Grams, M. E. (2016). Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Internal Medicine JAMA Intern Med, 238.
  2. Northuis, C., Bell, E., Lutsey, Pm. George, K., Gottesman, R., Mosley, Tom., Whitsel, E., & Lakshminarayan K. (2023). Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study. American Academy of Neurology.
  3. Blank ML, Parkin L, Paul C, Herbison P. (2014). A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int., 86(4):837-844.
  4. Sierra F, Suarez M, Rey M, Vela MF. (2007) Systematic review: proton pump inhibitor–associated acute interstitial nephritis. Aliment Pharmacol Ther.,26(4):545-553.
  5. Antoniou T, Macdonald EM, Hollands S, et al. (2015) Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ Open, 3(2):E166-E171.
  6. Klepser DG, Collier DS, Cochran GL. (2013) Proton pump inhibitors and acute kidney injury: a nested case-control study.BMC Nephrol, 14:150.
  7. Leonard CE, Freeman CP, Newcomb CW, et al. (2012) Proton pump inhibitors and traditional nonsteroidal anti-inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury. Pharmacoepidemiol Drug Saf, 21(11):1155-1172.
  8. Xie, Y., Bowe, B., Li, T., Xian, H., Balasubramanian, S., Al-Aly, Z. (2016). Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. Journal of The American Society of Nephrology, 27.
  9. Kang, J. H., & Kang, J. Y. (2015). Lifestyle measures in the management of gastro-oesophageal reflux disease: Clinical and pathophysiological considerations. Therapeutic Advances in Chronic Disease, 6(2), 51-64.

Can Daily Aspirin Prevent Both Heart Disease and Cancer?

Laura Gottschalk, Ph.D., Sasha Milbeck & Meg Seymour, PhD

Many adults take a low-dose aspirin (or “baby” aspirin) to prevent heart disease and possibly cancer. The most recent data indicates that in 2017, 23% of U.S. adults over 40 who did not have heart disease took low-dose aspirin to help prevent developing it.1 About 23% of people taking “baby” aspirin daily reported that they did so without a doctor recommending it. Should you take daily aspirin to prevent heart disease? The recommendations depend on your age, as well as other risk factors.

In April 2022, the United States Preventive Services Task Force (USPSTF) issued updated recommendations that people over 60 should not start taking low-dose aspirin, because the benefits do not outweigh the risks.2 For those ages 40-59 with a 10% or more chance of developing heart disease over the next 10 years, the USPSTF says the data are unclear. So, the decision to start taking low-dose aspirin should be made with one’s physician, weighing the risks (which vary among individuals) against the small benefits.

These recommendations are notably different from the USPSTF’s 2016 recommendations, which did not recommend against starting to take low-dose aspirin for those ages 60-69. The 2016 recommendations also recommended adults ages 50-59 with a 10% or more chance of developing heart disease over the next 10 years and who were willing to take daily aspirin for those 10 years begin to do so.3

What Are the Benefits and Risks?

Why have the recommendations changed over time, and what do we now know about the cardiovascular benefits of taking low-dose aspirin that we didn’t know a few years ago? A 2019 study combined the results of 13 clinical trials, all comparing daily aspirin to placebo or to no treatment.4 The combination study, called a meta-analysis, analyzed over 164,000 patients, who were followed for an average of five years. The researchers found that patients who used daily aspirin had fewer heart attacks and fewer ischemic strokes. However, the authors also found that people who took daily aspirin were more likely to have intracranial bleeding (inside the skull) and major gastrointestinal bleeding.

The USPSTF reviewed the research on low-dose aspirin in order to develop their recommendation, and drew similar conclusions.5 The analysis of over 161,000 patients found that people taking daily aspirin reduced their chances of a having at least one major cardiovascular event such as a heart attack or stroke by 2.5%. And yet, the analysis also found that people taking “baby” aspirin were not less likely to die from heart attacks or strokes. In addition, people taking daily aspirin were 1% more likely to experience major bleeding, such as gastrointestinal bleeding that resulted in a transfusion, hospital admission, intracranial bleeding, or death.

It is important to know who is most likely to experience harmful bleeding. Research has shown that the increased chances of bleeding begins relatively soon after starting to take “baby” aspirin on a daily basis, and it increases with age. Bleeding is more common among men, smokers, people with high blood pressure, people with liver disease, people with diabetes, and people with a history of gastrointestinal problems, such as peptic ulcer disease.5 Taking certain medications can also increase the risk of bleeding, including nonsteroidal anti-inflammatory drugs (such as ibuprofen or naproxen), steroids (such as prednisone), and anticoagulants (such as warfarin). We agree with the USPSTF recommendation that these factors make dangerous bleeding more likely for anyone taking daily aspirin.

In a 2023 meta-analysis of 16 studies, researchers compared the risks and benefits of low-dose aspirin in adults who did not have cardiovascular disease who use statins to those who did not use statins.6 Statins are a group of drugs that lower LDL or “bad” cholesterol by helping the body slow down cholesterol production and rev up cholesterol removal. Researchers found that at every level of cardiovascular disease risk, the chances of developing major bleeding complications from daily aspirin were greater than the chances of the aspirin preventing heart attacks or other cardiovascular problems. That was true for patients taking low-dose aspirin alone or with a statin. For that reason, statins alone are now considered safer than low-dose aspirin for preventing heart attacks even for those with little or no risk.

According to the USPSTF, the benefits of daily aspirin use are different for someone in their 60s or 70s who has already been taking low-dose aspirin compared to someone in their 60s or 70s who is considering whether to start to take daily aspirin. For people already taking daily aspirin, the benefits become smaller with age, because the chance of serious bleeding increases with age.  Modeling data suggest it may be a good choice to consider stopping taking regular aspirin after around 75. However, stopping daily aspirin can lead to a “rebound” effect where the chances of cardiovascular events increases slightly within the first few weeks that is maintained for at least one year.7 The increased risk means that about one out of every 74 patients (1.4%) who discontinue use will experience a cardiovascular event, such as heart attack or stroke. The risk is higher than 1.4% for people who previously had a CVD event and lower for those who took daily aspirin to prevent a first CVD event.8 If you are currently taking daily low-dose aspirin and want to consider stopping, speak with your doctor about how to safely taper your use.

Does Daily Aspirin Prevent Cancer?

The USPSTF also reviewed scientific studies of whether daily low-dose aspirin can help prevent colorectal cancer. They found that four studies following patients for up to 10 years found no evidence that taking daily aspirin reduced the chances of developing colorectal cancer.5

The 2019 paper mentioned above also found that daily aspirin did not reduce the chances of dying of cancer, compared with no aspirin.4 In fact, one clinical trial in that meta-analysis (called ASPREE: Aspirin in Reducing Events in the Elderly) found that individuals who took aspirin were slightly more likely to die from cancers. Researchers analyzed the overall chance of dying from 14 common cancers, including colorectal cancer, and found that 3.1% of the participants taking daily aspirin had died a cancer-related death at five years follow-up, compared with 2.3% of those taking a placebo.9 This is a small difference but is it conclusive? Most participants in the ASPREE trial had never used low-dose aspirin regularly before joining the study, and that made it impossible to determine if taking “baby” aspirin regularly for many years is likely to increase or decrease the chances of dying of cancer.

However, a more recent, longer-term study, published in 2021 found that people who started using low-dose aspirin regularly at a younger age and who continued after age 70 were less likely to develop colorectal cancer than people who didn’t use low-dose aspirin.10 That study combined 2 large studies that included almost 95,000 patients.

The USPSTF 2022 analysis notes that the evidence about daily aspirin and colorectal cancer is highly variable, with randomized clinical trials showing no benefit and some long-term observational studies showing some possible benefit.11 Given these inconsistent results, the USPSTF does not recommend that older patients begin taking low-dose aspirin for the sole purpose of preventing colorectal cancer.

The Bottom Line: Should I Take a Daily Aspirin?

Overall, the choice to begin taking low-dose aspirin (or to continue if you are already taking it) should be a decision that you make with your healthcare provider, after weighing the potential risks and benefits. The research described above is a good reminder that aspirin is a drug that has risks even at low doses. For many people, aspirin’s risk of serious bleeding may outweigh the benefits of decreased cardiovascular events. However, if you have been taking low-dose aspirin, stopping to take it also has risks, especially if you previously had a cardiovascular event such as a heart attack or stroke. When discussing with your healthcare provider the possibility of taking daily aspirin, let them know:

  •       Your medical history and all the medicines you are currently using, whether they are prescription or over-the-counter,
  •       Any allergies or sensitivities you may have to aspirin, and
  •       Any vitamins or dietary supplements you are currently taking

To read our comments made to the USPSTF about their 2021 updates to their recommendation statement, click here.

Other Ways to Prevent Heart Disease and Cancer

In 2022, heart disease and cancer were the leading causes of death in adults in the United States.

To reduce your risk of heart disease, don’t smoke, exercise regularly, keep your cholesterol and blood pressure under control, and do what you need to do to prevent diabetes.  Being a man and being older also put you at risk, but those are factors you can’t control.

To reduce your risk of colorectal cancer, don’t smoke, don’t drink alcohol in excess, have a healthy diet, stay physically active, and maintain a healthy weight.  Being older, and having a family history of colon cancer, Crohn’s disease, or ulcerative colitis are the risk factors you can’t control.

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.


  1. O’Brien CW, Juraschek SP, Wee CC. Prevalence of aspirin use for primary prevention of cardiovascular disease in the United States: results from the 2017 National Health Interview Survey. Annals of Internal Medicine. 2019 Oct 15;171(8):596-8.
  2. Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease: Preventive Medication. April 26, 2022
  3. Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. April 11, 2016.
  4. Zheng SL, Roddick AJ. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: a systematic review and meta-analysis. JAMA. 2019;321(3):277-87.
  5. Guirguis-Blake JM, Evans CV, Perdue LA, Bean SI, Senger CA. Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Evidence Synthesis No. 211. Rockville, MD: Agency for Healthcare Research and Quality; 2021. AHRQ publication no. 21-05283-EF-1.
  6. Khan SU, Lone AN, Kleiman NS, Arshad A, Jain V, Al Rifai M, et al. Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories. JACC: Advances. 2023 Feb;100197.
  7.  Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J. Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Archives of Neurology. 2005; 62(8):1217-20.
  8. Sundström J, Hedberg J, Thuresson M, Aarskog P, Johannesen KM, Oldgren J. Low-dose aspirin discontinuation and risk of cardiovascular events: a Swedish nationwide, population-based cohort study. Circulation. 2017; 136(13):1183-92.
  9. McNeil JJ, Nelson MR, Woods RL, Lockery JE, Wolfe R, Reid CM, Kirpach B, Shah RC, Ives DG, Storey E, Ryan J. Effect of aspirin on all-cause mortality in the healthy elderly. New England Journal of Medicine. 2018; 379(16):1519-28.
  10.  Guo C, Ma W, Drew DA, et al. Aspirin Use and Risk of Colorectal Cancer Among Older Adults. JAMA Oncology. Published online January 21, 2021. doi:10.1001/jamaoncol.2020.7338
  11. Mora S, Shufelt CL, Manson JE. Whom to Treat for Primary Prevention of Atherosclerotic Cardiovascular Disease: The Aspirin Dilemma. JAMA Intern Med. Published online April 26, 2022. doi:10.1001/jamainternmed.2022.1365

Statement of Dr. Diana Zuckerman, President, National Center for Health Research, March 8, 2023

Today the FDA announced that 19 women were reported in medical publications who developed squamous cell carcinoma (SCC) in the capsule around breast implants. This is more than the 10 women that FDA reported in September. Several of the women died.  It is important to know that 24 cases of SCC have been reported to the FDA, but it is not known if these cases overlap with the 19 that were published or if some of the 24 cases were reported more than once. Some of the women had silicone gel implants, some had saline implants, some textured, some smooth.  Some of the women got breast implants for augmentation, others for reconstruction after mastectomy.  That means that all women with breast implants need to be aware of this risk, even though it may be rare.

Last September, the FDA also reported 12 cases of lymphomas different from anaplastic large cell lymphoma (ALCL) that were also caused by breast implants.  The agency has not updated those numbers.

Testimony of Dr. Diana Zuckerman About PEPAXTO FDA Advisory Committee Meeting on September 22, 2022

I’m Dr. Diana Zuckerman, president of the National Center for Health Research. We scrutinize the safety and effectiveness of medical products, and we don’t accept funding from companies that make those products.  Our largest program is focused on cancer.  My expertise is based on post-doc training in epidemiology and public health, and previous positions at HHS and faculty member and researcher at Yale and Harvard.

All of us want more treatment options for refractory cancers, but we want patients to be able to have confidence that FDA approval means a product is proven safe and effective.  The OCEAN study of 495 multiple myeloma patients has important information that was not available when the drug received accelerated approval. Even if some patients taking Pepaxto do well, it is only with a randomized controlled trial that we can determine if Pepaxto is helpful or if the patients would do better without it.

Our Center’s analyses support the FDA findings that the data do not confirm the indication.  In the randomized trial comparing Pepaxto to another treatment option, median survival was 5.3 months shorter, and the death rate was slightly higher.

The Sponsor says some patients do better but we agree with FDA that “Results from subgroup analyses cannot be used to conclude benefit in a subset of patients, when the overall patient population has shown a detrimental treatment effect.”

We also agree with the FDA that PFS is not improved and that “An anti-cancer therapy that prolongs PFS is not considered safe and effective if the therapy results in a detrimental effect on OS”

Public trust in the FDA has been weakened in recent years.  FDA standards matter to all of us.  Would you want your loved one to take Pepaxto rather than a superior treatment option?  Not all oncologists will be as knowledgeable about the data as those serving on this panel.

It concerns us that the sponsor continues to ignore FDA concerns, rely on shortcuts instead of better research, and that the company withdrew the drug in October but then rescinded the withdrawal.  Was this just a delaying tactic?  We agree with the FDA that the sponsor did not provide new data, and with Dr. Pazdur that FDA approval relies on solid information about appropriate dosage, which is lacking here.

Maybe Pepaxto would benefit some types of patients and better research is needed to prove that.  As FDA states, the preponderance of evidence from the prespecified analysis and in all other subgroups suggests an increased risk of death in patients and a potential for harm.”

We were pleased that the Committee voted 14-2 that the evidence does not support that the benefits outweigh the risks.

The FDA followed through and rescinded Pepaxto approval in December, 2022.

Why Are Celebrities Removing Their Breast Implants?

Amelia Murphy, Cancer Prevention & Treatment Fund

Every now and then, a new celebrity is in the news after announcing her decision to remove her breast implants. They speak out about the importance of loving yourself the way you are, they post some Instagram pictures of “the new me,” and the public eagerly reads the related articles in tabloid magazines.

But most of these women aren’t just talking about body image; they are getting their implants removed because of their health. Breast implants can make some women so sick that removal is their best hope for feeling like themselves again.  Several celebrities are trying to spread this information to the general public.

Crystal Hefner, Hugh Hefner’s wife, opened up about her breast implant horror story on Facebook. She announced her implants had been slowly poisoning her and causing unexplained back pain, cognitive problems, constant neck and shoulder pain, recurring infections, and many other symptoms. Once she removed her breast implants, she instantly felt an improvement and continues to feel better. [Read more about her story in this Forbes article]

Yolanda Foster, of Real Housewives fame, removed her breast implants when she found out her silicone implants had ruptured and were leaking into her body. The silicone was making the symptoms of her Lyme disease even worse. She felt much better once she removed her implants.

Linda Blair, actress in the horror movie The Exorcist, described her experience with breast implants as a nightmare. After removing her implants, she advocated for the FDA to make sure breast implants are actually studied to be safe.

Mary McDonough, a child star in The Waltons who appeared as an adult in shows such as ER and Will and Grace, attributes her autoimmune disease (lupus) to her breast implants. She was healthy before getting implants, and it was only after her implants were removed that she immediately started to feel better. She has been one of the most outspoken celebrities on the risks of breast implants.

Karen McDougal is a former Playboy Playmate and current model who made the decision to have her implants removed after months of feeling sick. She has spoken out about the risks of breast implants in USA Today and People Magazine.

Mariel HemingwaySharon Osbourne, and Stevie Nicks are just a few of the other celebrities who chose to remove their breast implants because of serious health problems.

Celebrities are bringing attention to the health problems that thousands of women with implants have suffered from for decades.

First, a little history:

Women have been getting breast implants since the 1960’s, and although silicone gel implants were drastically restricted for many years during the mid-1990’s through 2005 because of safety concerns, the FDA approved them again in 2006 based on short-term studies done by breast implant manufacturers. FDA also required the manufacturers to do larger, longer-term studies after that, in order to make sure they were safe (these are called post-market studies).

These longer-term studies had a lot of problems, and most women did not stay in the studies long enough to provide useful scientific information.  However, studies have shown that the longer women have silicone breast implants, the more likely they are to experience problems with them.  FDA reported that the studies found that as many as 1 out of every 5 women who get silicone breast implants for cosmetic reasons need to remove their implants within 10 years.[1] This number rises to 1 out of every 2 women if they got reconstruction after a mastectomy.[1]  Were the women who dropped out of the studies the ones that were more likely to have health problems, or less likely?  You can read more about the unanswered questions from these studies here.

Breast implants were approved by the FDA even though research showed that between 15% and 20% of first-time augmentation patients will need additional surgery to fix implant problems within 3 years, whether the implants are filled with silicone gel or saline. [2][3] The chances of needing additional surgery increases as time goes on — 28% of women are on the second set of implants after 3 years, and this number doubles when the women have their implants for 6 years. The percentage is even higher than that for mastectomy patients whose implants were for reconstruction.

What usually goes wrong?

  • Rupture: All breast implants will eventually break, sometimes within a few months or years, and usually within 10 years.
  • Capsular Contracture: This is when the breasts get firm, then hard, and they can be very painful. Breast implants are a “foreign body” and the natural response for most women is that their body forms scar tissue around the implant, inside their body, to protect their body from this “foreign invader.”  This is a natural process. However, it’s called capsular contracture when the scar tissue tightens or hardens around the implants and causes abnormal firmness, hardness, or pain.
  • Pain: Besides pain caused from capsular contracture (see above), breast implants can cause back, neck, and shoulder pain because of their weight. Leaking silicone gel can also cause a painful burning sensation.
  • Autoimmune issues:  Experts disagree on whether breast implants cause specific autoimmune diseases.  However, the fact that implants can cause cancer of the immune system (ALCL) certainly makes it more likely that implants can cause other autoimmune problems.  FDA scientists found that women with ruptured and leaking silicone gel breast implants were more likely to have fibromyalgia, a painful autoimmune disease.[5]  Many women have reported suffering from autoimmune symptoms such as joint pain, hair loss, dry eyes, or mental confusion after getting breast implants, and have also reported that these symptoms often improve or disappear after removing the implants. One study even showed the autoimmune symptoms got better for 3 out of 4 women after they removed their implants.[6]
  • Constant flu-like symptoms: Many women report feeling constantly tired or like they’re trying to get over the flu.
  • Learn more about complications from breast implants in FDA’s consumer handbook.

Besides health problems, some celebrities decide to remove their implants simply because they were annoying or embarrassing. Just to name a few, Heather MorrisHeidi MontagPamela AndersonVictoria Beckhamand Jane Fonda all removed their implants for this reason.

Plastic surgeons refer to breast augmentation as a very simple surgical procedure, and as a result many people think of breast implants as an insignificant surgery with few health risks.  Hearing about celebrities who removed their breast implants sometimes makes women think twice about getting them in the first place.  It helps remind all of us to do careful research before making any decision about putting something inside your body.


ALCL Update: In March 2017, the U.S. Food and Drug Administration (FA) updated its website to report that breast implants could cause a type of cancer of the immune system called Anaplastic Large Cell Lymphoma (ALCL). [4]  No celebrities have reported ALCL from their breast implants. .


Are you considering breast implants? Find out more information here.

Are you thinking about removing your breast implants? Find out more information here.

ALCL and Breast Implants: 2017 Update

Anna E. Mazzucco, PhD and Diana Zuckerman, PhD, Cancer Prevention & Treatment Fund

In March, 2017, the U.S. Food and Drug Administration (FDA) updated its website to officially report that breast implants could cause a type of cancer of the immune system called anaplastic large cell lymphoma (ALCL).  They stated they have received 359 reports of ALCL among women with breast implants.

The FDA’s announcement came 10 months after the disease was named breast implant associated ALCL (BIA-ALCL) in a  World Health Organization publication in 2016, and a few months after the and the National Comprehensive Cancer Network (NCCN) released the first worldwide oncology standard for the disease.  NCCN includes a guided algorithm for surgeons and oncologists to test for and diagnose the disease.  They concluded that any abnormal accumulation of fluid or a mass that develops near the breasts months after breast implants were implanted must be evaluated.

The oncologists also state that even if the BIA-ALCL is confined to the scar capsule that surrounds the implant and even if that capsule is totally removed through proper explant surgery, the patient must be followed for 2 years.  Here is the link to their guidelines:

Although rare, it seems that BIA-ALCL is not “very rare.”  In Australia, which can track medical problems from any kind of implants better than the tracking of implants in the U.S., they estimate that BIA-ALCL affects one woman per 1,000 with breast implants.  The estimates were much lower in the U.S., but there is no reason to think BIA-ALCL is less likely to develop in women in the U.S.  Given the dramatic increase in diagnoses in recent years, it is clear that BIA-ALCL was under-diagnosed and under-reported for many years.

The sooner ALCL is diagnosed, the more likely it can be treated easily and effectively by removing the implants and capsule.  At later stages, treatment includes chemo and is less likely to be successful, as specified by researchers at the well-respected MD Anderson Cancer Center in a medical journal in 2013. Their study followed women for 5 years and found that ALCL related to breast implants sometimes requires chemotherapy, and approximately 25% of the implant patients with the more serious type of ALCL died during the 5 years following their diagnosis.[1] Dr. Anna Mazzucco published a response to this study,[2] urging physicians to respond quickly and to check patients who have swelling near their implants for ALCL. This would require cytology testing rather than testing for bacteria. The authors of the original study also published a response to Dr. Mazzucco’s article, expressing similar concerns.[3]

For more information, see our summary of that study here.

ALCL caused by breast implants can result in swelling, which is often mistaken for an infection and treated with antibiotics. Antibiotics are ineffective against ALCL and the delay in timely and appropriate treatment for ALCL is dangerous.

Unfortunately, some health insurance companies have traditionally not covered the cost of medical tests or treatment for women with breast problems related to cosmetic breast implants. The published articles on ALCL clearly indicate that this can result in undetected cancer of the immune system (ALCL), which can be fatal. In addition, delays in treatment for ALCL can be extremely expensive for patients and their insurance companies; the companies would be required to pay for treatment for ALCL when it is eventually diagnosed at a later stage.


  1. Miranda RN, Aladily TN, Prince HM, et al: Breast implant–associated anaplastic large-cell lymphoma: Long-term follow-up of 60 patients. J Clin Oncol 32:114-120, 2014.
  2. Mazzucco, AE. Next Steps for Breast Implant-Associated Anaplastic Large-Cell Lymphoma. J Clin Oncol, 2014.
  3. Miranda RN. Reply to AE Mazzucco. J Clin Oncol, 2014. Early Release publication. June 16, 2014.

Good news for coffee drinkers: the health benefits outweigh the risks for most people

By Morgan Wharton, Jessica Cote, and Shahmir Ali

latte-249102_640Most Americans drink coffee every day.1 The caffeine in coffee helps us stay alert but also may cause jitteriness and interfere with sleeping. A few studies suggest that decaffeinated coffee also has health benefits, perhaps because of antioxidants or acids in the coffee bean.2

What Are The Health Benefits Of Drinking Coffee?

For years medical experts advised people to drink less coffee, mostly because of research suggesting coffee might increase the risk of heart disease. However, numerous studies conducted recently have discovered coffee’s unexpected health benefits. Like all well-designed research, most of these studies considered the impact of age, sex, body mass index (BMI), physical activity, tobacco use, and whether family members had developed cancer. By controlling for those factors, researchers made sure they could separate coffee’s impact on health from the effects of people’s lifestyle, family history, and previous health problems. However, the type of coffee you drink may influence its health benefits; a very large study from the UK published in 2022 found that adults who drank larger quantities of unsweetened or sugar-sweetened coffee were less likely to die from cancer in the subsequent 7 years, and also less likely to die from any cause during that time frame.3  However, drinking more artificially sweetened coffee had no impact on cancer or other deaths.

Colorectal Cancer

Meta-analyses are a kind of statistics that combine data from several comparable studies to make one very large study. These results are usually more accurate than any one study can be. Taken together, three meta-analyses suggest that drinking about four or more cups of coffee per day may reduce the chances of getting colorectal cancer by 11-24%.456

Endometrial (uterine) Cancer

Using data from 67,470 women who participated in the Nurses’ Health Study, researchers found that women who drank four or more cups of coffee per day were 25% less likely to develop endometrial cancer than women who drank only one cup of coffee per day. Compared to women who did not drink any coffee, those who drank four cups or more per day were 30% less likely to develop endometrial cancer. Decaffeinated coffee was just as effective as caffeinated coffee, but caffeinated tea did not lower the risk of endometrial cancer.7

Liver Cancer And Cirrhosis (Scarring of the Liver/Chronic Liver Disease)

One study found people who drank one or two cups of coffee per day had a slightly lower risk of getting the most common type of liver cancer compared to non-drinkers, but people who drank three or four cups of coffee were about half as likely as non-drinkers to get this kind of liver cancer. Meanwhile, people who drank five or more cups per day had an even lower risk than that (about one-third the risk of non-drinkers).8

Similarly, a study in Japan found a 76% decrease in the risk of that type of liver cancer in people who drank at least five cups of coffee per day compared to those who did not drink coffee. The strongest benefit was seen in individuals with hepatitis C, a disease which increases a person’s risk of developing liver cancer, although the researchers were not sure why.9

A study of 120,000 Americans over an 8-year period found a 22% decrease in the chances of developing cirrhosis for each daily cup of coffee. In Norway, a 17-year study of 51,000 citizens found that those who drank two or more cups of coffee per day were 40% less likely to develop cirrhosis compared to those who did not consume coffee.10

Skin Cancer

Using data from two enormous studies, the Nurses’ Health Study and the Health Professionals Follow-up Study, researchers found that men and women who drank more than three cups of caffeinated coffee per month were 17% less likely to develop basal cell carcinoma compared to people who drank less than one cup per month. Basal cell carcinoma is the most common and least dangerous type of skin cancer. Drinking decaffeinated coffee did not affect basal cell carcinoma.11

A 2014 study in the Journal of the National Cancer Institute found that the more coffee participants drank, the less likely they were to develop malignant melanoma over a 10 year period. Melanoma is the most dangerous form of skin cancer. Almost 450,000 whites, aged 50-71, participated in the study. Researchers found that drinking four or more cups of coffee per day was linked to a 20% lower risk of getting malignant melanoma. Once again, drinkers of decaffeinated coffee lost out. Their risk of getting melanoma was no different from that of non-coffee drinkers. Coffee drinking, however, did not affect the least dangerous form of melanoma, called melanoma in situ.

Remember that no matter how much coffee with caffeine you drink, the best way to prevent skin cancer is still to limit your time exposed to the sun and ultraviolet light! 12

Type 2 Diabetes

People in Finland consume more coffee than almost any other nation, and a study of 14,000 people over 12 years  found that men who drank 10 or more cups of coffee daily had a 55% lower risk of developing type 2 diabetes than men who drank 2 cups of coffee a day or fewer.  Even more dramatic, women who drank 10 or more cups per day had a 79% lower risk of developing type 2 diabetes than those who drank fewer than 2 cups daily.13

A different Finnish study of 5,000 sets of identical twins found that individuals who drank more than seven cups of coffee per day had a 35% lower risk of type 2 diabetes than their twins who drank two cups or fewer per day.14 Because identical twins are so biologically similar, the difference in disease risk is very likely caused by coffee consumption levels. Studies of fewer people in other countries have found less dramatic but similarly positive results.

Parkinson’s Disease

A study of more than 8,000 Japanese-American men found that men who did not drink coffee at all were three to five times more likely to develop Parkinson’s disease within 30 years than men who drank four and a half cups or more of coffee per day.15


Because suicide may be related to alcohol intake, medications, and stress levels, suicide studies took those factors into account.  A 10-year study of 128,000 people in California found that the risk of suicide decreased by 13% for every additional cup of coffee consumed per day. Even one cup of coffee per day seemed to reduce the risk of suicide. A different 10-year study of 86,000 women found a 50% lower risk of suicide for those who drank two or more cups of coffee per day compared to women who did not drink coffee.16

Brain Power and Aging

A study of 676 healthy men born between 1900 and 1920 suggested that coffee helped with information processing and slowed the cognitive decline typical of aging. Cognitive functioning was measured by the Mini-Mental State Examination, a 30 point scale. Men who regularly consumed coffee experienced an average decline of 1.2 points over 10 years, while men who did not drink coffee saw a decline of 2.6 points over 10 years. Men who drank three cups of coffee per day declined only 0.6 points over 10 years.17

Even old mice are sharper with caffeine: a study using a mouse model of Alzheimer’s disease showed that coffee actually reversed the cognitive decline and slow-down in processing that occurred with age. Mice given caffeine in their water showed signs of recovering their memory during testing.18

What about the risks?


Two separate studies found that 300 mg of caffeine (two to three cups of coffee) decreased a woman’s chances of getting pregnant by more than a third. This same amount of coffee also increased the chances of women having low birth-weight babies by 50%. These studies took into account potentially influential  factors such as contraception used in the past and infertility history.19

Hip Fracture

According to data from the Nurses’ Health Study, women aged 65 and over who drank more than four cups of coffee per day had almost 3 times as many hip fractures over the next six years as women who did not drink coffee. Researchers took important factors into consideration such as how much calcium the women consumed each day.20

Parkinson’s Disease among post-menopausal women taking estrogen-only hormone therapy

Other researchers used data from the Nurses’ Health Study to evaluate the risk of Parkinson’s disease among women who drank coffee while using estrogen medication after menopause. For women who were NOT using estrogen therapy, those who drank four or more cups of coffee per day were about half as likely to develop Parkinson’s disease as women who did not drink coffee. For women who did use post-menopausal estrogen, however, those who drank four or more cups of coffee were about twice as likely as those who didn’t drink coffee to develop Parkinson’s.21

Heart Disease

Two different meta-analyses found that people who drank five or more cups of coffee per day were 40-60% more likely to develop heart disease compared to those who did not drink coffee at all. Other studies have also shown that high coffee use (five to ten cups per day) increases the risk of heart disease, while moderate consumption (three to four cups daily) was not associated with a higher risk. Only coffee drinkers who consumed more than nine cups a day had a greater risk of dying from heart disease.22 It is important to consider that people drinking close to 10 cups of coffee a day are likely to have other health problems, such as stress or sleep deprivation, and this could contribute to higher risk of heart disease and death regardless of coffee use.

Bottom line

For most people, drinking coffee seems to improve health more than harm it. Many of coffee’s health benefits increase with the number of cups per day, but even one cup a day lowers the risk of several diseases. However, women who want to get pregnant or already are pregnant and women over 65 should probably limit their coffee intake because, in their case, the risks may outweigh the health benefits.

Even though many studies show coffee has benefits, it’s still not clear why. How can one popular beverage help metabolism (for example, lowering the risk of type 2 diabetes) and also protect against a range of cancers? Until further research can solve that puzzle, most adults should continue to enjoy their cup (or two, or three) of Joe. Finally, remember that nearly all studies on coffee and health have been done on adults. Coffee may affect children and teens differently.

Gene Therapy May Provide Hope for Patients with Advanced Leukemia

Margaret Dayhoff-Brannigan, Cancer Prevention and Treatment Fund

Acute Lymphoblastic Leukemia (ALL) is difficult to treat in children and adults. The most effective treatment is a stem cell transplant, but for patients whose cancer comes back after stem cell treatments, or who cannot be treated with a stem cell transplant, there are very few other options.

A study published in the prestigious New England Journal of Medicine in October 2014 tested a new treatment on terminally ill patients, 78% of whom survived at least 6 months.23

What is Acute Lymphoblastic Leukemia?

ALL is a cancer of the blood and bone marrow. It is the most common form of leukemia in children. In a healthy person, blood consists of red blood cells which carry oxygen and nutrients, platelets that help wounds to heal, and white blood cells which help the body fight infection. These different types of cells are made from stems cells in the bone marrow. In a patient with ALL, there are too many abnormal white blood cells that do not work properly to fight infections. These patients do not have enough red blood cells and platelets, and that can cause anemia or excessive bleeding. 24

Treatment Options

Currently there are four treatment options for ALL patients. Chemotherapy is a common cancer treatment that uses drugs to kill cancer cells. Radiation therapy is a treatment for cancer that uses x-rays or other forms of radiation to kill cancer cells. Targeted therapy uses very specific drugs or substances to identify and attack only cancer cells without causing harm to normal cells. Chemotherapy with stem cell transplant combines chemotherapy (and sometimes radiation) to kill cancer causing stem cells in the body, and then replaces them with a donors stem cells.2 How successful the treatment is usually depends on how old the person is when they are diagnosed and the amount of white blood cells the person has. ALL has a cure rate of 80-90% in childhood cases, but only about 40% in adults. Approximately 1,170 adults and 270 children die of ALL each year.25

Two Promising New Treatment for Patients with Relapsed ALL

There are two promising new treatments, but more research is needed before doctors will know more about which patients are most likely to benefit and before these treatments will be widely available.

Researchers at two hospitals in Philadelphia used an experimental treatment for ALL on 25 children and 5 adults.1 The children were seen at Children’s Hospital of Philadelphia by Dr. Shannon Maude and Dr. Stephan Grupp and their colleagues. The adult patients were treated at the University of Pennsylvania School of Medicine under the care of Dr. Noelle Frey. These patients all had relapsed several times or had failed to respond to any treatment. All had only a few weeks or months to live. The scientists took blood from each patient and separated out the white blood cells. These cancerous white blood cells were then genetically modified so that they could recognize and attack the diseased cells that cause the leukemia. The genetically modified cells were then put back in the patient using a blood transfusion.

One month after the treatment, 27 of the 30 patients were in remission. However, as the study continued, 7 of the 27 had a relapse, anywhere from 6 weeks to 8.5 months after treatment. More relapses are expected as the study continues.

Overall, 78% of the patients in the study were still alive 6 months after treatment, which was much longer than would have been expected without the gene therapy.1 When the results were written up for publication, one patient had survived two years after therapy. However, approximately half the patients had received the treatment less than 7 months earlier (some as little as 1-2 months earlier), making it impossible to calculate the average number of months of survival for the 30 patients.

Although patients were selected for the study if they were not eligible for stem cell transplant, several became eligible after gene therapy improved their health, and successfully underwent stem cell transplants or another treatment. However, the patient who has survived for two years did so without additional treatment.

We expect that a subsequent publication will give 2-year follow-up data for all 30 patients.

A different and also successful treatment for patients with relapsed or untreatable ALL was published recently by a different group of scientists at the Memorial Sloan-Kettering Cancer Center in New York City. They used a similar method to modify the genes in the patients’ white blood cells. However, this treatment was only effective at giving patients a short period of remission while they were waiting for a stem cell transplant. None of the patients in this study could be cured without also receiving a stem cell transplant.26 In contrast, the treatment studied by doctors in Philadelphia is the first to offer the possibility of a long reprieve or even possibly a cure in patients who had very little time left to live.


A Special Focus on Carcinoid Tumors

Anna E. Mazzucco, Ph.D., Cancer Prevention and Treatment Fund

Although textbooks call them rare, the incidence of carcinoid tumors is on the rise.  In 1973, carcinoid tumors were diagnosed in only 8.5 people per million; by 1994 this number more than quadrupled to 38.4 per million.27 This increase could be due to several factors, such as more sensitive detection, increased awareness, and the larger number of Americans over the age of 50.28   However, the cause of the increase is unclear, and these tumors can be life-threatening.  When they grow and spread, these tumors often affect organs that show no symptoms until late in the disease. Like almost all cancers, earlier diagnosis is very important for the overall prognosis.

Carcinoid tumors belong to a larger medical category called neuroendocrine tumors, which are named for their “neural” (i.e. information-sensing) and “endocrine” (i.e. hormone-related) functions.  Carcinoid tumors are a particular type of neuroendocrine tumor, named to reflect being “carcinoma-like” or “carcinoid” due to their microscopic similarities to more aggressive cancers.  They are considered distinct types of tumors because they are usually very slow-growing.29  Instead of being named for the organ in which they occur, the unifying feature of carcinoid tumors is that they start in a particular kind of neuroendocrine cell, which can be found in several different organs.  That is why carcinoid tumors can be found in the stomach, appendix, colon, lung, and other organs, and also why the symptoms, treatment and prognosis of carcinoid tumors can also vary so much between patients.  The location and size of the tumor determine a lot about its characteristics and also which treatments are best.

Risk Factors

Scientists and physicians are still working to understand carcinoid tumors.  We know that there are a few traits which can increase a person’s risk of having a carcinoid tumor.  These include:

  • Age (50 and older)
  • Gender (female)
  • Family history of multiple endocrine neoplasia type I (MEN1)
  • Conditions which cause low stomach acid production, such as Zollinger-Ellison syndrome, pernicious anemia, and atrophic gastritis
  • Smoking (for atypical lung carcinoid tumors)


As carcinoid tumors can form in many different organs, symptoms vary by location, and can be similar to those of other health issues.  However, if you experience any of these symptoms for several days, call your doctor.

For carcinoid tumors of the gastrointestinal system, symptoms may include:

  • diarrhea or constipation
  • nausea
  • abdominal or rectal pain
  • rectal bleeding

For carcinoid tumors of the lungs, symptoms may include:

  • chest pain
  • wheezing or shortness of breath
  • skin discloration that looks like stretch marks
  • unexplained weight gain in the midsection or upper back

Another feature of carcinoid tumors which makes them different from other tumors is that they can cause symptoms which at first may seem unrelated to each other.  In these rare cases (only about five percent of all carcinoid tumor cases), the tumor can cause unusually high amounts of hormones in the blood.30  This situation, called carcinoid syndrome, could result in symptoms such as:

  • flushing
  • heart palpitations
  • large changes in blood pressure
  • swelling of legs and feet


Diagnosis may rely on several sources of information, such blood and urine tests, imaging tests such as CT or MRI, endoscopy, or biopsy.  Endoscopy allows closer visual examination of the tumor with a tiny camera passed through the digestive tract.  During an endoscopy, a biopsy sample may be collected, which is very small amount of tissue removed for analysis.  Based on this information, physicians will often classify carcinoid tumors as either typical or atypical.  They will also define a tumor as having “local”, “regional spread”, or “distant spread”, based on how far a tumor may have grown beyond its original location.


Surgery is often used as the first treatment for carcinoid tumors.  If the tumor hasn’t spread, surgery can cure the cancer.  Surgery may also be combined with other treatments to reduce the tumor and the symptoms.  If the tumor has spread to the liver, which is quite common, it can be surgically treated by blocking the artery to the liver with chemotherapy or injected polymer beads. Liver tumors can also be treated by radiofrequency (radiowaves) or cryotherapy (using cold to destroy cancer cells).2

The drugs most commonly used to treat carcinoid tumors are hormone therapies called somatostatin analogues, such as octreotide (Sandostatin) and lanreotide (Somatuline Depot), which are given as daily or monthly injections, respectively.  These drugs work to block the growth of the tumor and the hormones it may produce, and can be effective for long periods of time, although the dose may need to be increased over time.  Newer versions of these drugs, such as pasireotide, are being developed and compared to the older drugs to determine which are more effective, and for whom.   Other treatments are being developed that use these same drugs to deliver radiation directly to cancer cells, such as in MIBG therapy.   A different drug also used to treat carcinoid tumors is interferon (Intron A, Pegasys), which uses the body’s own immune defenses against the tumor.2  New studies are evaluating the safety and effectiveness of combining hormone therapies such as octreotide with interferon to see if they work better together.  Radiation and traditional chemotherapies are not usually helpful for slow-growing carcinoid tumors.  However, some carcinoid tumors (often called “atypical”) with higher growth rates (or high “proliferation index”) may respond to them.  Studies of combinations of chemotherapy drugs are being conducted to find out which are most effective.

As scientists are learning more about carcinoid tumors, new drugs called “targeted therapies” are being developed, which are based on a detailed biological understanding of the tumor.  Clinical trials are being done to investigate these new drugs for carcinoid tumors, such as everolimus (Afinitor), sunitinib (Sutent), azaspirane (Atiprimod), IGF-R1 blockers (AMG 479), and VEGFR and Akt inhibitors (such as Tricirinine, Axitinib, Votrient, Avastin, Cometriq, Ziv-aflibercept) 2,31  Everolimus and sunitinib have been approved by the Food and Drug Administration for the treatment of advanced pancreatic neuroendocrine tumors, but FDA will not approve these drugs for carcinoid tumors until clinical trials are completed to show whether they are safe and effective for those tumors.   Studies have shown that carcinoid tumors produce high amounts of particular proteins related to cell growth, including IGF-R1 and VEGFR2, and new drugs are being developed to block these molecules.32   Another new treatment, YF476, is being tested specifically for stomach carcinoid tumors.

If you are undergoing treatment for a carcinoid tumors, up-to-date information about clinical trials can be found here.   A healthy diet, exercise, and emotional support can also be helpful during treatment for cancer.  If you have questions about your treatment or want to know more about your treatment options, ask your doctor lots of questions and consider seeking another opinion until you receive the information you need.

Testimony of Dr. Jennifer Yttri at FDA Advisory Committee on Tivozanib

May 2013

I am Dr. Jennifer Yttri and I am speaking on behalf of the Cancer Prevention and Treatment Fund of the National Research Center for Women & Families. Our non-profit research center scrutinizes medical data, evaluating scientific evidence of benefits and risks for patients.  We analyze and review research and provide objective and understandable health information to patients, health care providers, and policy makers.  Our organization does not accept funding from pharmaceutical companies and therefore I have no conflict of interest.

Today’s fundamental question is whether the one completed Phase 3 clinical trial is enough to approve the new drug tivozanib as a treatment for patients with renal cell carcinoma.

FDA guidelines recommend two trials that support efficacy of a drug. In some cases, FDA will approve a new drug based on only one trial if that trial shows a significant improvement over existing therapy. In the FDA’s own words: “A conclusion based on two persuasive studies will always be more secure than a conclusion based on a single, comparably persuasive study. Reliance on only a single study will generally be limited to situations in which a trial has demonstrated a clinically meaningful effect on mortality, irreversible morbidity… and [when] confirmation of the result in a second trial would be practically or ethically impossible.”

The NDA submitted for tivozanib relies on one phase 3 study comparing tivozanib to sorafenib. While tivozanib was shown to increase progression free survival by 3 months in patients with renal cell carcinoma, it did not improve overall survival. In fact, there was a non-significant lower overall survival for tivozanib, suggesting the drug may actually harm patients more than it helps them. This one study alone is not enough to meet the FDA’s guidelines for drug approval.

In addition, the study results have inconsistencies that raise red flags about the research and about the drug itself.

1.       Patients receiving tivozanib had increased progression free survival, so why were they more likely to die in the first 30 days due to disease progression, compared to sorafenib. This does not make sense. The deaths in the first 30 days could be due to chance, but the disease free survival could also be due to chance.  More research is needed to clarify the risks as well as the long-term benefits.

2.       FDA noted that 70% of sorafenib patients stopped taking the drug at least temporarily and 44% ended up with a reduced dose. This is much higher than other studies – for example one study highlighted by the FDA had only 14% interruption and 10% reduction.  There is no logical explanation for this, but these unusual problems could make sorafenib seem inferior to tivozanib, when in fact it might be superior.

These inconsistencies may be due to chance or to irregularities in how the studies were conducted in other countries.  Standard of care and assessment of disease varies in the US and other countries, and fewer than 10% of patients enrolled in the trial were in the US.  We agree with the FDA reviewer that it is preferable to enroll US patients, so that the study reflects the disease burden and treatment in the US and can provide better insight into treatment outcomes for US patients.

Regardless of the reason for the inconsistencies in the study, a second, independent, phase 3 study would help determine the safety and efficacy of this drug for treatment of renal cancer.

We urge you to recommend that the FDA require the sponsor to complete a second trial to confirm the positive effect of tivozanib on PFS; address the concern over lower OS; and provide better information on how generalizable the results are in the US population. Based on the data provided, there are no ethical concerns with requiring another trial. With the additional information, the FDA can make an informed decision as to whether tivozanib meets their standards of safety and efficacy.  That is not possible based on this one study with such inconsistent results.