Memorial Sloan Kettering is taking a leading role in helping more people with bladder cancer keep their bladder. One new technique looks at a tumor’s genes to find people who will respond to other treatments.
Bladder cancer can be treated very effectively with surgery. For people with a tumor that has invaded the muscle of the bladder wall (stage II) or even spread through the wall to surrounding muscle and tissue (stage III), the standard treatment is chemotherapy followed by removal of the bladder.
The surgery to remove a bladder is called a radical cystectomy. It can be done either as open surgery or with minimally invasive methods. A radical cystectomy provides the best chance of a cure, but bladder removal is a major operation. Losing a bladder is a permanent change that can significantly affect a person’s quality of life.
“I see a lot of patients who say, ‘I came to you because I don’t want to lose my bladder. If you tell me I absolutely have to, I’ll accept it, but I want to exhaust every possibility before that,’” says Memorial Sloan Kettering urologic surgeon Harry Herr. “Over the years, people have been sent here for a radical cystectomy after a diagnosis, and we have been able to preserve the bladder.”
In some cases, doctors can remove the tumor through the urethra with a cystoscope. Afterward, the patient receives a combination of chemotherapy and radiation. Although this approach spares people from major surgery, the combination of chemotherapy plus radiation can lead to significant side effects. If the bladder cancer returns after this treatment, people must then have a radical cystectomy.
The Toll of Bladder Removal
Most people with bladder cancer are older — the average age of diagnosis in the United States is 73. Dr. Herr explains that people in this age group have a harder time tolerating and recovering from the effects of a major surgery. A radical cystectomy typically requires a hospital stay of five to seven days. There are sometimes complications from manipulation of the bowel during surgery, such as blockage or impaired function.
Older people are less likely to be candidates for a neobladder. (This is a procedure in which a new bladder is created from part of the small intestine.) As a result, they often must have urine diverted through an opening in the abdomen to a pouch worn outside the body. They are also at a higher risk for urinary tract infections.
MSK is taking a leading role in studying approaches that allow more people with muscle-invasive cancer to preserve their bladder. The key is carefully selecting those who will respond well to other treatments.
“We have the expertise in pathology, radiology, oncology, and surgery to choose people who will have a lower risk of their cancer returning,” Dr. Herr says.Back to top
Genetic Weak Spot: DNA-Damage Response Mutations
Important insights have been made in recent years by looking at the genes of tumors from people with bladder cancer who had chemotherapy followed by surgery. Researchers at MSK and elsewhere noticed that people with tumors that had genetic changes called DNA-damage response (DDR) mutations responded especially well to chemotherapy before surgery.
They did so well, in fact, that during the radical cystectomy that followed, little to no tumor was found. This suggests that the chemotherapy destroyed most, if not all, of the cancer in the bladder. Furthermore, this group of people also had a very low risk for their cancer ever coming back.
Research has shown that cancer cells with DDR mutations are unable to repair the DNA damage caused by chemotherapy. About 20% of bladder cancers have these mutations.
“Using this genetic information, we could potentially save patients a major surgery and manage their bladder cancer with chemotherapy alone,” MSK medical oncologist Gopa Iyer explains. “That would be of dramatic benefit and a major shift in the way we approach the treatment of these people.”
A clinical trial set to begin later this year will test this bladder preservation approach in patients with muscle-invasive bladder cancer. The trial will be led by Dr. Iyer. It is funded by the National Cancer Institute and will involve multiple sites around the United States.
An important factor in the trial is analysis of patients’ tumors with MSK-IMPACT™. This genetic-sequencing test was developed at MSK. All participants, regardless of location, will submit a sample for MSK-IMPACT testing for the DDR gene mutation. While waiting for the results, the patients will receive 12 weeks of chemotherapy.
After the chemotherapy concludes, patients found to have certain DDR mutations will be examined by cystoscopy to make sure no invasive disease remains. People with no invasive disease will be able to choose to keep their bladders. They will then be closely monitored with cystoscopies and radiology scans every few months.
People who do not have a DDR mutation or who have invasive cancer remaining after chemotherapy will have a cystectomy.
Dr. Iyer says the trial will also provide valuable information about other genes that predict sensitivity or resistance to chemotherapy. Not everyone who responds well to chemotherapy has a DDR gene mutation, so other mutations are likely involved. For some people, knowing there is an absence of mutations predicting sensitivity to chemotherapy can also be important.
“We could spare these patients the toxicity of chemotherapy,” Dr. Iyer says. “For them, maybe a cystectomy is the best option, or some other treatment, such as immunotherapy.”Back to top