Fox Chase Cancer Center researchers are tackling a challenging question: is active surveillance instead of total bladder removal ever a safe option for muscle invasive bladder cancer (MIBC) patients who have received chemotherapy?
The new trial, nicknamed the “RETAIN Bladder” study, uses a risk-adapted approach that uses clinical features as well as genetic mutations in the cancer cells to predict whether chemotherapy will be effective in preventing recurrence or metastases of bladder cancer without having to remove or radiate the bladder, says Fox Chase’s Daniel M. Geynisman, MD, the study’s lead researcher.
“Removing the bladder, which is the standard of care for MIBC, has many quality-of-life ramifications,” says Geynisman. “If we can develop predictive biomarkers to figure out who responds to chemotherapy and who doesn’t, we can apply our recommendations in a more nuanced way.”
“I have had patients cry in my office because they didn’t want to lose their bladder and have to rely on a bag. Participants in the study tell me they have prayed for this solution,” says surgeon Rosalia Viterbo, MD, FACS, who is participating in the research. “Although about 70 percent of patients will probably need a cystectomy eventually, this gives patients a bit more time before that and it preserves the bladder for the 30 percent whose disease responds well to the chemotherapy.”
The research is being funded by Fox Chase/Temple Health and Caris Life Sciences, which is conducting the genetic sequencing. Researchers also come from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center of Baltimore, Md., and the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pa.
Recent studies, including one led by Fox Chase’s Alexander Kutikov, MD, FACS, and David Y.T. Chen, MD, FACS, have shown that some 30 percent of cystectomy patients have no evidence of MIBC following AMVAC chemotherapy, which is an Accelerated course of treatment using 4 chemotherapy drugs: Methotrexate, Vinblastine, Adriamycin, and Cisplatin (AMVAC). Other studies indicate that mutations in DNA damage repair/response genes are predictive of pathologic response to neoadjuvant chemotherapy at the time of cystectomy, with those patients achieving pT0 disease (i.e., no cancer left at the time of bladder removal) demonstrating excellent long-term survival.
The RETAIN Bladder study offers a decision tree to clinicians. For patients whose pre-chemotherapy biopsies show one of four particular genetic mutations and then in whom imaging and cystoscopy shows no evidence of disease after chemotherapy, active surveillance is initiated. For patients who show some degree of residual disease or who do not demonstrate one of the key mutations,, the decision tree recommends that the physician and the patient choose whether to pursue additional intravesicle therapy, chemoradiation or a cystectomy. For patients who show stage 3 disease, a cystectomy is recommended.
While the primary objective is to evaluate the metastasis-free survival at two years for all patients, secondary objectives include assessing the following:
- The rate of any urothelial carcinoma recurrence in active surveillance patients.
- Bladder preservation rates with neoadjuvant AMVAC chemotherapy and subsequent risk-adapted treatment.
- The feasibility of an Endoscopic Tumor Quantification System.
- Quality of life with neoadjuvant AMVAC and subsequent risk-adapted treatment (EORTC QLQ-BLM 30, SHIM, FSFI, AUA symptoms score).
- Genomic correlates and mutations in urinary cell-free DNA.
- Toxicity in each treatment arm.
“We want to emphasize that most patients will still need to go on to have a cystectomy or chemoradiation for definitive therapy to the bladder,” he says. “But we are hoping that for some patients whose disease shows the biomarkers that predict a good response to treatment we can avoid surgery or radiation and learn who can safely avoid having their bladder removed.”
Viterbo agrees. “I am enrolling as many of my patients as possible in the study, as long as they are a candidate for the bladder cancer surgery. After we’ve done the genetic sequencing and the chemotherapy, the patient and I discuss their results and the potential for active surveillance. We are able to make a good decision together, even if it is to do a cystectomy, because we can apply the risk assessment approach from the study.”
Geynisman adds that the trial is an example of how the Fox Chase urologic cancer team works seamlessly together to initiate important clinical trials and provide novel options for patients.
“We have an incredibly cohesive and collaborative team-based approach to cancer care,” he notes. “Together, we are combining clinical data with molecular or genomic data to see if we can make a smarter decision with our patients about cystectomies and bladder cancer care in general.”
Learn more about treatment for bladder cancer at Fox Chase.