Some of the early signs of bladder cancer can be easy to dismiss. Lower back pain. Painful or frequent urination. These can point to any number of benign conditions, including urinary tract infection and kidney stones. It’s the unsettling discovery of blood in the urine that sends most people with bladder cancer in search of medical advice.
Bladder cancer is the ninth most common cancer worldwide. About one in four cases is considered muscle-invasive bladder cancer (MIBC), meaning the tumor has penetrated the bladder’s muscular wall or has spread outside the organ. MIBC is aggressive and typically requires radiation or complete removal of the bladder (a procedure called a cystectomy). At the time of first diagnosis, most bladder cancers are non-muscle-invasive. They arise in the bladder lining and tend to respond well to a combination of surgery, immunotherapy and chemotherapy.
Immunotherapy and chemotherapy are frequently delivered directly into the bladder. Although those treatments remain a mainstay of bladder cancer care today, their effectiveness is limited; a patient can hold these drugs in their bladder for only so long. “After a few hours, the patient voids the medication,” explains Chris Cutie, M.D., Vice President, Disease Area Leader, Bladder Cancer, Johnson & Johnson Innovative Medicine.
Researchers at Johnson & Johnson have come up with a novel investigational option to help address this problem: a targeted releasing system that is placed in the bladder and stays there for weeks at a time, continuously exposing urine and bladder tissue to therapy. It’s just one of the new approaches the company is working on to improve the lives and longevity of patients with bladder cancer. We spoke to Dr. Cutie, as well as Sumeet Bhanvadia, M.D., Senior Director, Johnson & Johnson Innovative Medicine, to learn more about this disease and the new treatments that are changing the way patients fight it.
1.
Smoking is the single biggest risk factor associated with bladder cancer. In fact, half of all bladder cancer cases can be linked to cigarette use. It’s easy to see why: After tobacco’s cancer-causing substances (carcinogens) get absorbed into the bloodstream, they’re filtered by the kidneys and then collect in the urine, exposing the bladder to high levels of toxic chemicals, which can damage the DNA in the cells lining the bladder.
Bladder cancer may actually be driven in some part and in some forms by androgen receptors.
But cigarettes aren’t the only culprit. Exposure to other types of chemicals can also raise a person’s risk. “People who work with hair dye in salons tend to have higher rates of bladder cancer,” says Dr. Cutie. And those who work with the kinds of toxic dyes, paints and solvents often used in heavy industry—like steelmaking—also face a higher chance of developing the disease.
Men carry a higher risk for developing bladder cancer than women and are three times more likely to get it. Used to be, experts thought that was because more men smoke and work in industrial jobs, but that thinking is changing, Dr. Cutie says. Research suggests that the gender disparity in bladder cancer rates may be partly attributable to hormones. “It looks like bladder cancer may actually be driven in some part and in some forms by androgen receptors,” Dr. Cutie says, referring to proteins on the surface of cells that bind to male hormones, such as testosterone.
Androgen hormones and androgen receptors play a role in immune function; to fight cancer—or any other disease or invader—healthy immune function is critical. “When I was in medical school, we were trained to look at the bladder as this simple storage organ and nothing more,” Dr. Cutie says. “But that view has shifted. We now know it’s also an immunogenic organ that plays an important role in immune recognition and immune signaling.” Researchers are still learning about the androgen receptor’s role in bladder cancer.
2.
Currently, there is no recommended screening for bladder cancer. But researchers are exploring whether it makes sense to screen high-risk groups like smokers and former smokers.
Most bladder cancers are urothelial in origin (also called transitional-cell because the cells change shape) and arise on the surface of the cells that line the urine-facing side of the bladder. Among those, most are non-muscle invasive, slow-growing and highly treatable. Once the cancer enters the bladder muscle or spreads to lymph nodes or beyond, however, it becomes harder to treat, Dr. Cutie says.
Chemotherapy can be effective, but because many patients are older and have other health problems, it isn’t always tolerable. A cystectomy also requires creation of a urinary diversion made of intestine; overall, it’s a complex operation that carries significant risks for elderly people and one that has a significant impact on quality of life. According to Dr. Bhanvadia, about 60% of patients who have their bladder removed will suffer complications within the first few months of surgery. “Overall, half of people with muscle-invasive bladder cancer will develop metastases within 5 years, even if they have received comprehensive treatments,” she adds. “Whether cancerous cells are found in the lymph nodes at the time of surgery has the biggest impact on survival outcomes, which is why early diagnosis has a huge impact on patient outcomes.”
3.
Caught early, bladder cancer can be managed. But it’s prone to recurring—which puts patients on the hook for follow-ups for the rest of their lives. “Bladder cancer is currently incurable, so patients have to be followed forever,” says Dr. Cutie. “That means sending in periodic urine tests and having your bladder inspected every three months with a cystoscope, or camera, which is burdensome, costly and uncomfortable.”
Not surprisingly, a significant percentage of patients with bladder cancer suffer from mental health issues, such as anxiety and depression. “When you check these patients and say to them, ‘Hey, I didn’t see anything on exam today,’ they smile and give you a high five—and then they realize they need a follow-up appointment in three months,” Dr. Cutie says. “You can see their faces fall.”
4.
In the mid 1970s, researchers made a big discovery: Bladder cancer appeared to respond to immunotherapy. BCG (short for bacille Calmette-Guerin), a vaccine originally developed in the early 1900s for tuberculosis, could be altered in a way that helped the body’s immune system recognize and kill bladder cancer cells. In 1990, BCG became the first immunotherapy for cancer approved by the FDA. For more than 30 years, it’s been the standard of care.
And yet, following that history-making advancement, progress in the treatment of bladder cancer slowed to a crawl. “For decades, bladder cancer research was a wasteland,” Dr. Cutie says. “There was very little innovation.”
Taking the chemotherapy agent and putting it into this innovative system that allows for continuous and low-dose delivery may improve effectiveness, while at the same time minimizing side effects to the patient.
Even today, late-stage bladder cancer requires radical treatment with the removal of the bladder. Patients who undergo cystectomy must adapt to life after surgery with a urinary stoma, a bag that collects urine outside of the body.
Treatments for earlier-stage bladder cancer have been slow to evolve, too. BCG and chemotherapy have been used for decades; traditionally, patients received these therapies by having them injected through a tube placed into the bladder through the urethra. A major limitation of this approach is that while these medications do have the capacity to kill these bladder cancer cells, the medication is only in contact with malignant cells for a few hours, limiting the effectiveness.
Dr. Cutie and his colleagues knew there had to be a different way to deliver potent bladder cancer therapies. Based on results from ongoing clinical studies, a version of the aforementioned targeted delivery system, which allows low doses of chemotherapy to be released in the bladder slowly over weeks, received Breakthrough Therapy Designation from the FDA for potential future use in patients with BCG-unresponsive, high-risk, non-muscle-invasive bladder cancer who are ineligible for or don’t want cystectomy.
“Taking the chemotherapy agent that we know is effective against bladder cancer cells and putting it into this innovative system that allows for continuous and low-dose delivery, may improve effectiveness, while at the same time minimizing side effects to the patient,” Dr. Bhanvadia says. “This could make a meaningful difference for patients.”
5.
An approved systemic treatment for patients with advanced or metastatic urothelial cancer whose tumor has a specific abnormal gene works by blocking the activity of the gene in cancer cells and in healthy cells throughout the body. “But treatments are only effective if they work, and are also well tolerated,” says Dr. Bhanvadia. As such, researchers and physician-scientists at Johnson & Johnson are also studying ways to administer this targeted medicine that may reduce side effects without compromising effectiveness. This includes a targeted releasing system that delivers the drug directly into the bladder, again, with sustained slow delivery.
No two cancer patients have the same genetic profile, and tailoring their treatment to their unique characteristics may improve their outcomes. As the emerging field of precision medicine grows, and as additional, gene-specific therapies become available, patients will have more options. That’s a huge win for patients, says Dr. Cutie.
