5 Things to Know About Bladder Cancer

Ariel Harsinay

Disclosures

November 29, 2018

Bladder cancer is the most common of the urothelial cancers and was the sixth most commonly diagnosed cancer in the United States in 2017.[1] This year, it is estimated that 81,190 patients will be diagnosed with bladder cancer in the United States. The US Food and Drug Administration (FDA) has approved six new immunotherapies in the past few years, leading to a rise in clinical trials testing the efficacy of these new treatment methods, primarily relative to or in conjunction with standard surgical procedures for treating bladder cancer.[2] In addition to research on new immunotherapies, advancements in research relating to the prognosis of bladder cancer are coming to the fore.

1. A model that considers six factors can predict survival for patients with advanced bladder cancer.

Gregory Russell Pond, PhD, and colleagues[1] from McMaster University in Ontario, Canada, have developed a model that considers six prognostic factors in order to predict the survival rate of bladder cancer patients. This model is specifically targeted toward the use of the immunotherapy atezolizumab, one of the six therapies approved by the FDA in recent years. Atezolizumab was approved as a treatment for those who are ineligible for cisplatin-based chemotherapy.[2] This model was developed using data from 405 patients in two clinical trials that investigated the use of atezolizumab. Various factors were tested and six prognostic factors were significant in predicting the survival rate of advanced bladder cancer patients. The six factors included anemia, LDH level, neutrophil-lymphocyte radio, blood platelet count, liver metastasis, and ECOG performance status, or ability to perform daily tasks. If patients had none or one of these six factors, the average estimated survival was 19.6 months. For patients with two to three factors, the average estimated survival was 5.9 months; and for those with four or more factors, the average estimated survival was 2.6 months. In addition to assessing these six prognostic factors, the research team investigated PD-L1 status, which is correlated with the effectiveness of atezolizumab as an immunotherapy. Pond and his colleagues hope that the model will be confirmed by larger datasets and that it can be an effective tool in clinic, especially in assessing which patients are the best candidates for atezolizumab immunotherapy.

2. There has been an increase in the use of trimodal therapy despite reports that radical cystectomy is less costly and leads to greater survival.

Despite guidelines recommending radical cystectomy as a treatment method for bladder cancer, there has been a resurgence in trimodal therapy, also known as "bladder-sparing" therapy. In order to compare the two treatment methods, Ashish Kamat, MD, and colleagues[3] at The University of Texas MD Anderson Cancer Center in Houston studied the Medicare data of 3200 bladder cancer patients. These patients were all at least 66 years old and had been diagnosed with T2 to T4a stage bladder cancer between 2002 and 2011. Out of the 3200 patients, 752 had undergone trimodal therapy and 2488 had undergone radical cystectomy treatments. After controlling for clinical and sociodemographic aspects, there were 687 patients for each therapy group. It was observed that the group that had received trimodal therapy had significantly decreased survival. While there was no apparent difference in cost initially, by 120 days there was a cost difference of $64,000. When equating these metrics to the total US population of bladder cancer patients, trimodal therapy was associated with $335 million in superfluous spending. While the radical cystectomy group either had the operation alone or in conjunction with chemotherapy or radiotherapy, the patients who underwent trimodal therapy were always treated by chemotherapy or radiotherapy afterwards. Kamat told Reuters Health that this study confirms that radical cystectomy is the safest and most cost-effective treatment even when trimodal therapies are accompanied by other treatments.

Regardless of these results, some physicians still believe that a wide array of treatment methods should be considered on the basis of the specific patient. In an editorial responding to this study, David Cahn, DO, a urologist from the Fox Chase Cancer Center in Philadelphia, stated that, "While provocative, these data do not provide sufficient evidence to support [radical cystectomy] as the primary treatment option for all patients with muscle-invasive bladder cancer. Despite attempts to adjust for selection biases, prior studies have illustrated that different methods of risk adjustment and more inclusive definitions of bladder preservation therapy influence survival outcomes. It is clear that until prospective data exist, choosing the ideal treatment strategy requires patient-centered, individualized decision making."[4]

Other studies have considered factors beyond cost and survival rate, such as assessing the quality of life of patients with trimodal therapy versus radical cystectomy. A study by Trevor Royce and colleagues[5] at Massachusetts General Hospital in Boston used a Markov model to simulate life outcomes and observed that there is an increased quality of life associated with trimodal therapy. This study is one of many that has contributed to the conversation on preserving the bladder with trimodal therapy for specific patients despite the overarching issues of increased cost and lower survival demonstrated in studies like Kamat's. Trimodal therapy is often a consideration for patients with little or no presence of hydronephrosis, or in patients with solitary tumors or good bladder function, among other factors. The University of Erlangen in Germany, Massachusetts General Hospital, and the University of Paris all came to the conclusion that candidates who completely respond to trimodal therapy (61%-87% effectiveness) can experience long-term survival, and if it is observed that any bladder cancer remains after a postoperative cystoscopy, then cystectomy should be used.[6]

3. Checkpoint inhibitors for the treatment of urothelial cancer in patients with low PD-L1 status have been associated with decreased survival rates.

In 2017, the FDA granted accelerated approval for pembrolizumab for patients who are not able to receive cisplatin-based chemotherapy but have metastatic or locally advanced bladder cancer.[2] During this year's conference of the American Society of Clinical Oncology (ASCO), however, reports of decreased survival rates associated with the use of checkpoint inhibitors led the FDA and European Medicines Agency (EMA) to send out warnings to use caution when considering these therapies to treat patients with urothelial cancers.[7] The KEYNOTE-361 study was one of the clinical trials that led to these warnings.[8] In this trial, a third of participants received pembrolizumab, one of the six immunotherapies recently approved by the FDA; a third of participants received pembrolizumab with chemotherapy; and a third of participants received chemotherapy alone. The second clinical trial that contributed to the warnings was IMvigor130.[9] Out of the 1200 participants being tested, one group received atezolizumab in conjunction with either gemcitabine and cisplatin or gemcitabine and carboplatin; one group received a placebo in conjunction with atezolizumab and with either gemcitabine and cisplatin or gemcitabine and carboplatin; and the third group received atezolizumab alone.

Both of these studies demonstrated that the use of atezolizumab or pembrolizumab as monotherapies can lead to decreased survival rates in comparison to patients who are also receiving chemotherapy with the checkpoint inhibitors. The FDA and EMA warnings advised against using these therapies as first-line treatments. In addition, the EMA stated that only patients with a PD-L1 level status greater than 5% should be considered as candidates for atezolizumab, and only patients with PD-L1 expression and a combined positive score of 10 or more—defined as the total number of PD-L1-positive cells (tumor, lymphocytes, and macrophages) divided by the total number of tumor cells—should be considered as candidates for pembrolizumab.

Elizabeth Plimack, MD, chief of genitourinary medical oncology at the Fox Chase Cancer Center, noted that these clinical trials have led to some confusion. While the FDA approved these drugs for patients who are ineligible for cisplatin-based therapy, these studies included a mix of cisplatin-based therapy–compatible and cisplatin-based therapy–ineligible participants. She also emphasized the wide array of currently available PD-L1 tests; the ones used in the clinical trials may not be the same ones that patients are receiving in the community. Plimack recommended that patients who are not eligible for cisplatin-based therapies receive a combination of carboplatin and gemcitabine until more information is released from the FDA and EMA.

4. Among BMI, weight, diet, vitamin supplements, and physical activity, only weight was found to be a significant lifestyle factor that can increase the risk for bladder cancer recurrence.

A meta-analysis by Ellen Westhoff, PhD, and colleagues[10] at Wageningen University in the Netherlands investigated lifestyle changes that bladder cancer patients may make and their effectiveness in terms of recurrence and cancer progression. Various factors, like smoking, weight, BMI, and exercise and dietary habits, were systematically reviewed. While previous studies have observed an association between smoking and the development of both muscle-invasive and non-muscle-invasive bladder cancers, there have not been conclusive results regarding whether smoking puts patients at risk for progression of bladder cancer. Besides smoking, other lifestyle factors have not been widely investigated in the past. This meta-analysis reviewed 14,126 articles and found that 31 provided BMI and dietary factors necessary for this analysis. A BMI in the category of overweight or obese was associated with an increased risk for bladder cancer recurrence compared with patients who were normal weight, but not with an increased risk for progression of the disease. BMI, dietary habits, exercise habits, physical activity, and the use of supplements provided inconsistent or inconclusive results. The research team proposed a possible explanation for the role of weight in recurrence of bladder cancer: local changes induced by obesity, such as altered levels of insulin, steroid hormones, cytokines, adiponectin, leptin, and insulin-like growth factor-1. In addition, the research team suggested that body composition was probably more relevant than BMI because BMI does not differentiate between muscle mass and fat mass. Because no strong conclusions were drawn, no recommendations can be made from this study; however, this meta-analysis emphasized the need for more cohort studies that investigate the role of lifestyle factors in bladder cancer prognosis.

5. Previously the bladder was thought to be a sterile environment, but active research predicts that it is possible to prevent onset of or treat bladder cancer by influencing the urine microbiome.

Until recently, it was believed that urine and the bladder itself were sterile. During the Human Microbiome Project, the first large-scale project to map the human microbiome, the bladder was not investigated because this belief.[11] In 2012, researchers from the Stritch School of Medicine at Loyola University demonstrated that urine is not sterile but rather contains various types of bacteria. The hypothesis that urine is not sterile had not been proven until recently because the bacteria present in urine does not show up in standard culture dishes in lab tests.[12] As a result of these findings, researchers have begun to investigate the role of these bacteria on various functions of the bladder, including the prognosis of bladder cancer. It is estimated that microbial agents can contribute to up to 20% of human malignancies, and because bladder cancer is the ninth most frequent malignant disease, it has been suggested that the human microbiome may influence the onset and progression of bladder cancer.[13]

A study released by Viljemka Bučević Popović, PhD, and colleagues[14] at the University of Split in Croatia aimed to characterize and compare the microbiome of the bladder in patients with bladder cancer versus controls in order to investigate the role of microorganisms in bladder cancer pathogenesis. Urine samples were collected from 36 male participants, 23 of whom were able to provide sufficient and proper-quality DNA for sequencing. Of these 23, 12 had bladder cancer and 11 were age-matched controls. After sequencing, 10 bacterial phyla, 19 classes, 26 orders, 61 families, and 107 genera were identified. Major differences were not observed between the bladder cancer group and the control group; however, several operational taxonomic units (OTU)—clusters that represent a unit of bacteria species—were overrepresented in the bladder cancer group. One of the OTUs overrepresented in the bladder cancer group was the Fusobacterium. Fusobacterium is also found in laryngeal, breast, esophageal, and pancreatic cancer tissue, and has been associated with cell proliferation and the inhibition of NK cell cytotoxicity and T-cell activities. These findings suggest that the bacteria weakens the immune system, which explains its high prevalence in cancer tissue. This study was unable to draw strong conclusions, however, and cited the need for further evaluation.

Another recent study that investigated the role of the urinary microbiome with bladder cancer was conducted by Peng Wu and colleagues[15] at Southern Medical University in Guangzhou, China. A total of 60 samples were obtained, 35 from males with bladder cancer and 25 from male nonneoplastic controls. The results demonstrated that the group with bladder cancer had a much greater bacterial richness. This richness was also greater within the group of bladder cancer patients who were at higher risk for progression and recurrence. Two genera were found in high abundance: Acinetobacter, which has been reported to be extremely abundant in cattle with urothelial tumors of the bladder and also involved in biofilm formation; and Anaerococcus, which is often associated with urinary tract infections and inflammation. Biofilm formation and inflammation have been established in the initiation and progression of tumors in a plethora of neoplastic diseases, such as colorectal cancer.[16] These findings suggest an association between the urinary microbiome and bladder cancer. Wu cited Popović's study and stated that differences in ethnicity, age, gender, and the number of cases are likely reasons for the widely different results.

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