Treatment for early-stage bladder cancer should be better

The bladder instillations with anti-cancer drugs that patients with early-stage bladder cancer receive leaves room for improvement. This is what Hans van Valenberg writes in his doctoral dissertation, which he defended on June 11, 2021. During his PhD program, he investigated methods to improve therapeutic bladder irragation in non-muscle-invasive bladder cancer.

With 6,500 new cases per year in The Netherlands, bladder cancer is one of the most common cancers. When this type of cancer is suspected, the doctor looks for malignant cells in the urine, and a cystoscopy of the bladder is done. If bladder cancer is present, (a portion of) the tumor is removed to determine how far the tumor has grown into the bladder wall. Based on this, the clinician determines the policy: if there is growth in the muscle layer, the entire bladder must be removed. If not, then removal of the tumor and subsequent treatment with drug-infused bladder instillations is sufficient.

This current treatment for non-muscle-invasive bladder cancer leaves room for improvement. "Despite additional treatment with bladder instillations, more than half of the patients have recurrent disease," says Hans van Valenberg. During his doctoral studies, he investigated the effectiveness of potentially new treatment options. "In up to one fifth of patients, the tumor continues to grow despite the bladder instillation. The bladder then has to be removed radically" This is a major operation with serious consequences for the patient.

Longer exposure time

Van Valenberg therefore investigated new ways of extending the exposure time of tumor tissue to drugs. One such way is a temperature-sensitive gel containing the drug. "A bladder instillation is normally based on water with a drug dissolved in it," Van Valenberg explains. "That is injected into the patient's bladder, who has to hold it in for as long as possible. That gives an exposure of a few hours at most." A longer exposure time likely results in a greater effect, so he investigated a gel that is liquid at room temperature, but solidifies in the body. "Only after three to four hours does the gel liquefy again and will the patient be able to void it out." Unfortunately, the effect was very strong but not different from standard in animal studies, Van Valenberg says. "The standard treatment worked very good as well. Possibly that was due to a dosing error in our experiments"

Another way for longer exposure that Van Valenberg investigated was a kind of intravesical device containing the drug. That way turned out to be safe. "You insert the device into the bladder, where it stays for a week. Then you can replace it with a new one." This way was safe in patients with bladder cancer, apart from mild symptoms, such as urge and pain when urinating. The effect of the treatment was measurable, although Van Valenberg emphasizes that his study focuses primarily on safety. "But the preliminary results give sufficient reason to do more research into this method."

Heat treatment

And the bladder instillations as it is currently used, is there more to tinker with? Certainly, says Van Valenberg. "It is possible to heat the bladder wall so that the drugs penetrate it better. That's already being done, with magnetron waves or a heated instillation of fluid. But it has never been properly proven whether there is a difference between these two techniques, and how that works." Van Valenberg therefore investigated both of these methods with animal experiments. The results showed that both techniques are approximately equally good at heating the bladder wall. With one small difference: the magneton waves reached the muscle layer around the bladder slightly better than the heat coming from the injected fluid. In people with bladder cancer, the heat treatment gave a markedly increased uptake of drug into the tumor.

A future treatment for non-muscle-invasive bladder cancer, according to Van Valenberg, will consist of not one, but several techniques. "The strength lies in the combination: both extending exposure and ensuring that the therapy is more penetrating. Ideally, you complement that with localized therapy, so that not the entire body has to suffer the side effects of the drug you're giving." An example of this is administering temperature-sensitive and encapsulated drug through the infusion. This is then released locally by heating the bladder. Yet Van Valenberg is clear: the treatments he has researched still need to prove themselves in patients. "That will still take at least ten years, provided we are not overtaken by other treatment methods. This kind of research requires a long horizon."