Bladder cancer, among the top 10 leading causes of cancer death in the United States, develops when cancerous cells begin to grow in the lining of the bladder. If the tumors become aggressive, they may penetrate through the various layers of the bladder, making the cancer more difficult to treat and often requiring bladder removal surgery (cystectomy).
Although many bladder cancer patients will need to undergo surgery, genitourinary cancer specialists are seeking new possibilities for retaining the bladder and avoiding a complicated, risky procedure for the patient. Along those lines, researchers at Fox Chase Cancer Center are conducting a new study — the INSITE trial — in hopes of identifying a better set of biomarkers to help clinicians more accurately identify patients with localized bladder cancer who can forgo a cystectomy.
The INSITE trial is led by Dr. Alexander Kutikov, Chair of the Fox Chase Department of Urology and the principal investigator of the study; and Dr. Matthew Zibelman, Associate Professor in the Department of Hematology/Oncology, who specializes in the treatment of genitourinary cancers. Together, they are committed to helping bladder cancer patients avoid unnecessary surgical removal of their bladders to maintain the best possible quality of life.
Bladder cancer patients may undergo chemotherapy before surgery to try to shrink tumors and make them easier to remove; for others, that may not be the standard of care. Using a combination of biomarkers, the INSITE trial aims to predict the presence of residual cancer (with or without the administration of neoadjuvant chemotherapy) and more accurately identify patients who may be able to avoid surgery altogether.
A cystoscopic evaluation — an examination of the bladder using a camera inserted through the urethra — may appear to show no visible disease even when cancer is present, as tumors can be embedded beneath the bladder lining, making them difficult to detect.
“The goal of INSITE is to create a test where we can say, ‘Your bladder is clean,’” Dr. Kutikov says.
To accomplish this goal and uncover any evidence of cancer cells that an examination with a scope might miss, INSITE combines a diagnostic panel including imaging, systematic endoscopy evaluation, a blood-based ctDNA assay, and a urine-based cell free DNA assay.
Several groups of patients are expected to be eligible candidates for the trial, Dr. Zibelman says:
• Patients with high-grade T1 urothelial carcinoma who elect for “early” cystectomy
• Patients with non-muscle invasive bladder cancer (NMIBC) who have relapsed or refractory/unresponsive disease after intravesical therapy and are recommended to have cystectomy
• Patients with cT2-T3 muscle invasive bladder cancer (MIBC) irrespective of receipt of neoadjuvant chemotherapy
With completion expected in 2-3 years, the INSITE trial is part of a pathway to benefit future bladder cancer patients with a better system and a better set of biomarkers for improved predictive accuracy. Every INSITE participant will go ahead with bladder removal surgery, but the research team will make note of whether they would have chosen not to have surgery based on their individual results.
Drs. Kutikov and Zibelman acknowledge that no tool can offer 100 percent certainty that all cancer has been cleared from the bladder. But with data from this trial — and given that bladder removal is a life-changing surgery — they hope to improve the accuracy of these evaluations, aiming to reach a level of confidence closer to 90 percent. “These are big surgeries that have significant risks,” Dr. Kutikov says. “We want to help patients make more informed decisions about whether going to surgery is worthwhile.”
The INSITE trial is considered a “sequel” of sorts for a similar study conducted by Drs. Kutikov and Zibelman several years ago. That study, which was published in 2021, used cystoscopy (an endoscopic procedure that examines the bladder lining) to attempt to predict which patients had residual disease in the bladder before undergoing surgery.
“We found that about one-fourth of the time, patients (who appeared to have clean bladders) still had tumors that had grown into the muscle,” says Dr. Zibelman, who was first author on that study. “That risk is too high. We couldn’t confidently say, ‘We don’t need to take your bladder out’ if there is a 25 percent chance they are still going to have cancer.”
In that previous study, the research team found limitations in using cystoscopy for predicting the presence of muscle-invasive bladder cancer in patients who were candidates for bladder removal. The authors noted that future efforts should be aimed at developing new imaging and biomarker methods to improve evaluations before the bladder is removed — which led the team to the INSITE trial to take the next steps.
“At the time, the idea was if we took all of these patients and, in a standardized way, looked into their bladder with surgeons who have a lot of expertise, we thought we could show that we can predict quite well who has disease left inside the bladder and who doesn’t,” Dr. Zibelman says.
This is important because about 30 percent of bladders that are removed do not harbor residual cancer after administration of chemotherapy. As Dr. Zibelman stated, the previous study showed that 25 percent of people who appeared to have clean bladders through cystoscopy actually harbored muscle-invasive disease that could be observed when the bladder was removed.
In the previous study, 61 bladder cancer patients underwent endoscopic assessments before receiving curative bladder removal surgery. The results of the evaluation were compared with pathology after bladder removal.
“There were submucosal tumors latent in the bladder walls that you could not see from the inside. It’s like looking in a room and there’s something behind the wallpaper,” Dr. Kutikov says. “That was a novel finding that was surprising, as I anticipated that the retrospective literature was overestimating the risk. But this helped us design further clinical trials and find research directions to overcome this barrier.”
That’s what the INSITE trial is designed to do. Developing more effective strategies will ideally lead to more accurate findings and more informed decisions in helping patients avoid unnecessary bladder removal surgeries.
“I think it will resonate that Fox Chase is doing something novel and not just operating on people, but trying to answer some very important questions,” Dr. Kutikov says.
Fox Chase is one of only two trial sites evaluating the diagnostic panel for INSITE. Former Fox Chase Urologic Oncology Fellow Jared Schober, MD, who is now Assistant Professor in the Division of Urologic Surgery at University of Nebraska Medical Center (UNMC), helped write the INSITE trial and is working to get a second site opened at UNMC.
The INSITE trial will benefit from the type of multidisciplinary collaboration inherent to Fox Chase’s Genitourinary Cancer Service. Medical oncologists, radiation oncologists, urologic oncologists and surgical oncologists all work together to tackle a question commonly seen in clinical practice.
“Physicians considering options for their patients with bladder cancer may want to refer them to Fox Chase,” Dr. Zibelman says. “Here, we are trying to answer the type of critical questions that can really make a difference.”
That’s the benefit of Fox Chase’s elite standing as an NCI-designated Cancer Center: Our research is led by extraordinarily talented scientists who work in an ideal environment for fundamentally important discoveries. With additional support from our partnership with Temple University Health System’s oncology research, treatment and prevention programs, Fox Chase research makes a world of difference in Northeast Philadelphia and all other communities that we serve.
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