Several studies have linked the diabetes drug Actos (pioglitazone) to bladder cancer. In June 2011, the FDA warned Actos users of an increased risk of bladder cancer.
Several recent studies have shown a much stronger link between Actos (pioglitazone) and bladder cancer than was indicated during clinical trials. In June 2011, the U.S. Food and Drug Administration (FDA) published a “Drug Safety Communication,” indicating that based on dose and duration of use, there exists a 40 percent increased risk of developing Actos bladder cancer.
During clinical trials, there was an indication that it could cause bladder cancer. However, most patients and their doctors were not aware of the possible link between Actos and bladder cancer. Since that time, there have been a number of studies linking the drug to bladder cancer, including one that showed an 83 percent increased risk for bladder cancer among Actos users.
Studies Linking Actos and Bladder Cancer
Three primary studies are most cited regarding Actos bladder cancer. The foremost is a 10-year study conducted by Kaiser Permanente Northern California. Sponsored by Takeda, the manufacturer of Actos, and required by the FDA, it started in 2002 after preclinical trials indicated an increase in urinary bladder tumors in rats. A five-year interim analysis indicated a 40 percent increased risk of bladder cancer in patients who took Actos for more than 12 months. That analysis was the basis for the FDA’s 2011 label and insert requirements regarding Actos bladder cancer. In August 2014, Takeda released a statement based on the final results of the study, claiming there was no “statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone.” However, the company did not release any further details.
Unlike other warnings about severe side effects, the update was to the Warnings and Precautions section and not to the Contraindication section. There was not an update to the drug’s black-box label indicating the risk of Actos bladder cancer.
The most widely known international study researching Actos bladder cancer was a three-year study by the French Medicines Agency from 2006 to 2009 that examined 1.5 million patients. It found a statistically significant indication that patients taking pioglitazone, the active ingredient in Actos, are at a greater risk of developing bladder cancer. Researchers stated their findings were very similar to those of the KPNC study.
In June 2011, the French Medicines Agency announced that it had suspended the use of Actos. Germany quickly followed suit, except it limited suspension to all new cases. In August 2011, Takeda formally withdrew Actos from those markets. In April 2011, the American Diabetes Association published a report that reviewed adverse drug reports filed with the FDA. Researchers stated they “found a definite signal for bladder cancer associated with pioglitazone use.”
One of the most recent studies on Actos and bladder cancer was published in the May 2012 issue of the British Medical Journal. Researchers studied 115,727 patients and discovered that Actos use increased the risk of bladder cancer by 83 percent. They also revealed that the risk increases with long-term use of Actos.
What is Bladder Cancer?
Bladder cancer is one of the most common types of cancer in the United States. According to the American Cancer Society’s latest statistics in 2015, an estimated 74,000 people received diagnoses and another 16,000 patients died from bladder cancer. Medical professionals predict an increase in the number of bladder cancer cases in the coming years.
Cigarette smoking and chemical exposure are among the leading causes of bladder cancer, the second-most common urological cancer in adults. Bladder cancer is more common among men than women, and afflicts more Caucasians than African-Americans. It is also known for its high recurrence rate.
But for patients diagnosed with bladder cancer, the silver lining comes in the form of statistics and new medical procedures:
|Bladder Cancer Statistics|
|About 80 percent of bladder cancer patients are diagnosed in the earliest stages.|
|The overall five-year survival rate is nearly 80 percent.|
|Innovative techniques allow an increasing number of patients to keep their bladder rather than having it removed.|
Bladder Cancer Causes
Among the risk factors for bladder cancer are advanced age, chronic bladder infections and treatment with certain types of medications. Those medications include cyclophosphamide, a common chemotherapy drug, and pioglitazone, the active ingredient in the Type 2 diabetes drug Actos.
Researchers say that because the leading cause of bladder cancer is smoking, it is one of the most preventable types of cancer. Studies show that cigarette smoking raises the risk for bladder cancer fourfold.
The medical theory about bladder cancer is that it is caused by an increased concentration of toxic chemicals in urine, which exposes the bladder to those chemicals. And that, over time, this exposure causes cancer. Bladder cancer is described as a signature disease of Actos, pointing to the theory of toxic exposure being a primary cause of the disease.
|Some occupations pose a stronger risk of daily exposure to workplace chemicals, which can lead to bladder cancer. Among them are:|
There are also some lesser-known causes, including arsenic and chlorine compounds found in drinking water, and sexually transmitted diseases, such as gonorrhea and human papilloma virus (HPV).
Bladder Cancer Incidence Rates
As medical studies observed Actos users for periods of 12 months, 24 months and longer, the patients’ risk of bladder cancer increased from about 30 percent after one year to as much as 83 percent after two years.
Takeda initiated a 10-year U.S. study of the drug conducted by researchers at Kaiser Permanente. In 2014, the drug maker announced that the study “did not show any statistically significant findings of increased risk of bladder cancer with long term use of pioglitazone.” These results sharply contrast with earlier data from a 5-year interim mark of the study that showed a higher incidence of bladder cancer among patients who used the drug. The company did not release any other details of the study but promised it would make the information available at a later date.
|Among its findings:|
|Less than 12 months of Actos use – No significant increase|
|12 to 24 months – 30 percent increased risk|
|More than 24 months – 50 percent increased risk|
|More than 48 months – Greater than 50 percent increased risk|
The studies consistently show the length of time patients take Actos has the strongest impact on increased risk of developing bladder cancer. The true long-term effect of Actos will not be known until the 10-year U.S. study releases its final results.
Most At-Risk Actos Users
Lifestyle choices can put people at a greater risk for bladder cancer, even if they don’t take Actos. In the general population, the majority of bladder cancer cases develop because of cigarette use.
|Actos users in the following groups are most at risk of getting bladder cancer:|
|Men: Incidences of bladder cancer occur more frequently in men than in women. In the Canadian study, one woman developed bladder cancer for every four men who got bladder cancer. In the general population, men are three times more likely to get bladder cancer than women.|
|Older than 65: The median age for Actos users who got bladder cancer was approximately 70 years old. This is similar to the general population, in which 72 percent of people who are diagnosed with bladder cancer are older than 65.|
|Smokers: 63 percent of Actos users who developed bladder cancer in the Canadian study were also smokers. For smokers, the increased risk of bladder cancer is already 50 percent. The carcinogens in cigarettes contribute heavily toward many types of cancer.|
|Obese: 59 percent of Actos users who developed bladder cancer were also obese. A person with a body mass index of more than 30 is considered obese. In the general population, obese people have a 40 percent increased risk of bladder cancer.|
|High glycated hemoglobin levels: The American Diabetes Association recommends people with diabetes reduce their long-term blood-sugar level to 7 percent. Of the Actos users who got bladder cancer, 52 percent of these people had a glycated hemoglobin percentage greater than 7.4 percent.|
|Alcohol drinkers: People who drink alcohol may be at greater risk of developing bladder cancer. Studies of the general population show a slight increase in bladder cancer associated with drinking. Six percent of Actos users who developed bladder cancer also used alcohol excessively.|
Symptoms of Bladder Cancer
Symptoms of bladder cancer develop quietly in a majority of people with the disease. Hematuria, also known as bloody urine, is typically the first sign of the disease. But because this symptom is usually painless and fleeting, most patients are either unaware of it or ignore it. Although the blood could be visible, it is most often undetectable unless under a microscope.For this reason, many patients don’t learn of their diagnosis until after a urine analysis.
Other common symptoms of bladder cancer, include:
- Frequent bladder infections
- Frequent urination
- Back pain
- Painful urination
While these are less severe, they should not be ignored.
Diagnosing Bladder Cancer
Because of the stealthy nature of bladder cancer, most patients are taken by surprise by a bladder cancer diagnosis. It often comes after testing for recurrent urinary tract infections (UTIs) or during a routine medical visit.
Once tumor markers are found in the urine, doctors order a series of other tests. These include an intravenous pyelogram (IVP), the standard imaging test for bladder cancer. Through this test, physicians can view the bladder and surrounding organs for evidence of cancer. Doctors also use CT scans, MRI scans and bone scans, as well as ultrasounds, for a more complete look at the bladder.
For a closer look at the inside of the bladder, doctors may perform a bladder biopsy. This is done with a long, flexible device called a cystoscope that is inserted into the bladder through the urethra. Small tissue samples are removed for laboratory examination.
Once bladder cancer is diagnosed, oncologists will stage the cancer using the tumor, node and metastases (TNM) system. With this, medical professionals can determine the extent of the cancer and the best course of treatment.
Bladder Cancer Treatment
While surgery, either alone or in combination with other treatments, is the standard for managing bladder cancer, researchers also are finding innovative ways to treat it. Treatments for this type of cancer typically are effective if the disease is caught early, before it spreads to muscles or other parts of the body.
|Treatment depends on the stage, or progress, of the disease.|
|Stage 0 through 1 treatments (non-muscle invasive):|
|Transurethral Resection (TUR or TURBT) – With the use of a cystoscope, surgeons are able to cauterize, or burn away, the destructive cancer cells.|
|Segmental cystectomy – In some early-stage patients, surgeons will remove a portion of the diseased bladder. The remaining bladder is sewn together.|
|Chemotherapy and immunotherapy – To ensure the cancer is killed, sometimes oncologists will order several rounds of chemotherapy or immunotherapy to impede the early-stage disease.|
|Stage II, III and IV treatments (muscle invasive)|
|Radical cystectomy – In this procedure, a surgeon removes the entire diseased bladder and replaces it with one of several urinary diversions. These include creating a new bladder from the intestines or creating a new urinary elimination system.|
|Chemotherapy and immunotherapy – Unless the patient is sickly or elderly, oncologists will prescribe either or both of these treatments to further destroy this spreading disease.|
|Clinical trials – Many oncologists will recommend that advanced-stage patients seek clinical trials for new and inventive ways to battle bladder cancer.|
Despite the best efforts of medical professionals, bladder cancer is known to reoccur in most cases. For this reason, medical professionals recommend that patients have check-ups every three months for the first three years after diagnosis and then every year thereafter.
For 90 percent of people who are diagnosed with this disease, the cancer is localized and has not invaded the muscle. That makes treatment for bladder cancer highly successful. For these patients, the surgical options for are not as invasive or severe. However, this type of superficial cancer is known to recur.
For the remaining 10 percent of patients, the surgical procedures tend to be more drastic. Invasive bladder cancer, as it is called, is known to spread to nearby organs and lymph nodes. Depending on the stage of the disease, doctors perform surgery to either remove some of the damaged tissue or the whole organ.
A major surgical procedure called a cystectomy is used on patients with advanced-stage bladder cancer, including cancer that has spread into the bladder walls. This is also used in recurring superficial bladder cancers.
In a partial cystectomy, also called a segmental cystectomy, surgeons remove the diseased portion of the bladder. This procedure is mainly used in a select group of patients with normally functioning bladders and one tumor. It is often followed by radiation or chemotherapy.
In a traditional surgical procedure for a partial cystectomy, the anesthetized patient lays face up on the operating table with a sterile surgical cloth covering most of the body. A catheter is placed in the bladder to remove urine. Using a scalpel, the surgeon cuts a vertical abdominal incision from the belly button to just above the pubic bone, and the bladder is exposed. At this point, some surrounding lymph nodes may be removed for further testing.
The surgeon then cuts open the bladder to check for the cancer damage. Then, the surgeon uses the scalpel to cut away the section of the bladder wall that contains the tumor and sews together the remaining bladder. The organ is filled with a saline solution to check for leaks. A drainage tube is placed in a separate incision in the pelvis to pull excess fluids from the body; it is later removed.
In laparoscopic and robotic-assisted partial cystectomies, the same general process as open surgery is used to cut away and remove the diseased portion of the bladder, but the surgeon’s hands never enter the patient’s body. Instead, the abdomen is inflated with carbon dioxide gas to create a space between the abdominal wall and the organs. For laparoscopic surgery, a surgeon uses two long-handled instruments and inserts them into the body through two small incisions. The excised piece of bladder is removed through one of those incisions. The use of laparoscopic tools is known to have a limited range for the surgeon.
For robotic surgery, four 2-inch incisions are made across the abdomen and four robotic arms perform the surgery. The surgeon directs the robot from a nearby computer console and video monitor. It is known to closely mimic a surgeon’s movements.
A radical cystectomy, which is used in the most invasive bladder cancer cases, removes the entire bladder and some surrounding tissue. In men, the bladder, seminal vesicles, vas deferens, prostate and nearby lymph nodes are removed.
In women, the procedure includes removing the bladder, ovaries, fallopian tubes and part of the vagina, as well as affected lymph nodes.
In the past, the only option following complete bladder removal was a stoma — a surgically created opening on the right side of the body where urine is expelled — and an external urine-collection bag. Today, reconstructive measures are in place to utilize existing organs to replace the bladder. The three most popular urinary diversions are the neobladder, continent diversionand ileal conduit.
Transurethral Resection of Bladder Tumor (TURBT)
About 75 percent of new cases of bladder cancer are non-muscle-invasive, meaning they are contained to the primary organ. Of those, 60 percent are low-grade and not likely to become aggressive or change the patient’s life expectancy. These cases are treated by removing the tumor through a surgical procedure known as Transurethral Resection of Bladder Tumor (TURBT).
In this procedure, a cystoscope — a sterile, flexible tube with a light and camera — is inserted through the urethra to search for abnormal areas of the bladder. The TURBT procedure can help a doctor diagnose early-stage cancer, and then he or she can remove the tumors at the time of discovery with a wire-loop tool or high-energy electricity. This procedure is done under general anesthesia to avoid discomfort, but patients usually can go home the same day.
Most patients with non-invasive bladder cancer are treated with TURBT and intravesical therapy, which allows medication to be delivered directly to the affected bladder, usually through a catheter. This is a localized treatment and only affects the targeted areas. It’s not effective if the cancer has spread deeper into the bladder walls or to other organs.
Because of the high rate of bladder cancer recurrence, a TURBT procedure and other surgeries often are followed by immunotherapy, which places medicines in the bladder through intravesical therapy. Immunotherapy, also called biologic therapy, uses substances in the body or those made in a laboratory to fortify the body’s natural defenses to fight the cancer.
The most common immunotherapy drug for bladder cancer is Bacillus Calmette-Guerin (BCG). “BCG is a weakened bacterium that attaches to the inside lining of the bladder and attracts the patient’s immune cells to the bladder to fight the tumor,” according to Cancer.net.
This liquid is placed with a catheter into the bladder, where it must remain for about two hours to promote the full benefit. This process is done once a week for six weeks, and booster treatments can be given at intervals afterward. A common maintenance treatment cycle is to place BCG every week for three weeks at intervals of six months for three years.
The use of BCG with a TURBT procedure is considered to be the most effective treatment for non-muscle invasive bladder cancer. Doctors specializing in treating bladder cancer say the use of BCG reduces the need to surgically remove the bladder later and it increases a patient’s overall survival rate.
As with most drugs, there are some side effects associated with BCG, though they mostly are short-lived. Within four hours of treatment, patients can expect to urinate more frequently, have pain with urination, and see blood in the urine. They may also have a fever and body aches. These side effects typically resolve within 48 hours.
If BCG alone does not slow the cancer, Interferon — made up of Roferon-A, Intron A and Alferon — can be given in combination with BCG.
Chemotherapy is another type of follow-up to a TURBT procedure that is used to help prevent a recurrence of bladder cancer by stopping the growth of the malignant cells. Chemotherapy can be delivered via intravesical therapy for non-muscle invasive bladder cancer or systemically for aggressive types of bladder cancer.
Patients with a low risk of recurrence are given one dose of the chemotherapy drug mitomycin right after the TURBT procedure. Mitomycin is a liquid that remains in the bladder for 30 to 60 minutes before being drained.
Patients with a higher risk of recurrence follow a regimen of one dose of mitomycin per week for six weeks and then may receive maintenance treatments every month for a year. These chemotherapy treatments are longer in duration, with the medicine remaining in the body for one to two hours.
Unfortunately, a powerful chemotherapy drug such as mitomycin does have side effects. These most often include bladder irritation, the urge to urinate frequently and pain during urination. A skin rash may also appear on the palms of the hands, soles of the feet, and genitals.
Systemic chemotherapy is cancer-killing medication that is delivered throughout the body via the bloodstream after being injected intravenously. It is used before cystectomy to help shrink the cancerous tumors or after the surgery to eradicate any remaining cancer cells.
“Recently, an important clinical trial has shown that the use of intravenous chemotherapy (the MVAC regimen) before radical cystectomy helps patients with invasive bladder cancer live longer. Based on this research it is considered the standard treatment,” Cancer.net reports.
The MVAC regime consists of four drugs: methotrexate, vinblastine, doxorubicin and cisplatin. Unfortunately, this standard of treatment comes with severe side effects, including bone marrow trauma, serious infections and even death.
According to research published in the journal Cancer, a two-drug chemotherapy regimen of gemcitabine and cisplatin (GC) successfully shrinks tumors prior to surgery with a lot fewer complications. Applications of GC currently are being studied in clinical trials.
Another promising chemotherapy treatment is the practice of combining these strong drugs with radiation to combat localized muscle-invasive bladder cancer. Researchers believe this regimen, called radiosensitizing, makes the chemotherapy more effective. In a British study, patients using radiosensitizing treatment had higher survival rates after two and five years.
Radiation is a third kind of therapy that can be used in combination with a TURBT procedure to eliminate bladder cancer while preserving the bladder. Radiation is the use of energy in X-rays or particles to kill malignant cells. This therapy can be delivered through a machine outside the body, called external-beam radiation, or from an implant, called brachytherapy.
External-beam radiation is the more common form of this therapy and is most often used in combination with chemotherapy. It is administered to the patient five days a week and only takes a few minutes each time. The course of radiation therapy usually varies from one to eight weeks, depending on the type of bladder cancer. Patients do not feel anything during radiation therapy.
Afterward, however, patients can expect irritation in the pelvic area, more frequent urges to urinate and bleeding from the bladder or rectum. In addition, they may experience fatigue, skin reactions and changes in bowel movements. Most of these side effects will be resolved when the treatment is completed.
Clinical trials may be the best hope for patients whose bladder cancer has metastasized, or spread to other parts of the body. These trials are controlled studies of the most progressive medicines and types of treatment and take place all over the world.
In addition, doctors will seek to control the symptoms of metastatic bladder cancer while slowing its growth. There is no cure for such an advanced stage of the disease, but palliative care can give patients a better quality of life.
Actos Bladder Cancer Lawsuits
In June 2011 the FDA announced that it was requiring a bladder cancer warning be placed on the Actos label and insert and gave legitimacy to many former Actos users’ claims that the drug caused them to develop bladder cancer.
After the FDA announcement, the number of Actos lawsuits and inquiries about the possibility of filing a lawsuit increased. With several hundred federal cases pending, both Takeda and plaintiff attorneys filed to move all pending Actos lawsuits to one district court. On Dec. 30, 2011, the U.S. Judicial Panel on Multidistrict Litigation in Georgia consolidated all federal Actos bladder cancer lawsuits to the U.S. District Court for the Western District of Louisiana.
In April 2015, Takeda agreed to settle about 5,000 federal Actos bladder cancer lawsuits and thousands more state cases for $2.37 billion dollars.