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Adjuvant chemotherapy improves OS in locally advanced bladder cancer
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Receipt of adjuvant chemotherapy appeared associated with improved OS in patients with locally advanced bladder cancer, according to the results of an observational study.
Although adjuvant chemotherapy does not currently serve as a standard of care in this patient population, these data support its adoption in patients who did not undergo neoadjuvant chemotherapy, according to the researchers.
Matthew D. Galsky
“A series of randomized clinical trials over the past 30 years have explored the efficacy of adjuvant chemotherapy in locally advanced bladder cancer,” Matthew D. Galsky, MD, associate professor of medicine and assistant professor of urology at Mount Sinai Hospital in New York City, and colleagues wrote. “However, the effectiveness of adjuvant chemotherapy in real-world patients with bladder cancer has not been comprehensively explored.”
Three prior clinical trials investigating adjuvant chemotherapy in patients with muscle-invasive bladder cancer have been terminated prematurely due to poor accrual, according to study background.
Thus, Galsky and colleagues sought to observe the effect of adjuvant chemotherapy in patients with locally advanced bladder cancer after cystectomy.
The researchers used the National Cancer Data Base to identify 5,653 patients with pathologic T3-4 and/or pathologic node-positive bladder cancer who underwent cystectomy. Of these patients, 1,293 received adjuvant chemotherapy, and 4,360 underwent observation.
OS served as the primary endpoint.
Patients who received adjuvant chemotherapy were younger (median, 64 years vs. 71 years; P ˂ .001). Those in the adjuvant chemotherapy cohort also appeared more likely to have private insurance (44% vs. 27%; P ˂ .001), live in a higher-income area (median income greater than $46,000 per year, 41% vs. 37%) and an area with more high school-educated residents (P ˂ .001 for both), and have lymph node–positive disease (64% vs. 32%; P ˂ .001) and positive surgical margins (16% vs. 13%; P = .0023).
A propensity score–adjusted analysis found that receipt of adjuvant chemotherapy improved OS outcomes (HR = 0.7; 95% CI, 0.64-0.76). This improvement persisted across all subgroups.
Further, the researchers observed a robust association between adjuvant chemotherapy and poor performance status.
“Assuming an HR of 1.3, poor performance status would not eliminate the significant survival benefit with adjuvant chemotherapy even if present in none of the patients in the adjuvant chemotherapy group and 100% of the patients in the observation group,” Galsky and colleagues wrote.
Study limitations included the inability to identify all potential confounding factors in propensity score–based analyses and the potential for selection bias inherent in retrospective studies.
“On the basis of level 1 evidence, neoadjuvant chemotherapy followed by cystectomy remains the preferred approach,” Galsky and colleagues wrote. “However, for patients who do not receive neoadjuvant chemotherapy, our results lend support to the use of adjuvant chemotherapy and may help facilitate shared medical decisions.”
Sumanta K. Pal
However, the lack of prospective data on the use of adjuvant chemotherapy may hinder its widespread utilization, Sumanta K. Pal, MD, assistant clinical professor of medical oncology and therapeutics research and director of the Kidney Cancer Program at City of Hope in Duarte, California, as well as a HemOnc Today Editorial Board member, and colleagues wrote in an accompanying editorial.
“The purist will be quick to acknowledge how unsatisfying it is to combine underaccruing prospective studies to form positive meta-analyses,” Pal and colleagues wrote.
“Admittedly, there is no substitute for valid prospective evidence,” they added.
However, the difficulties associated with conducting randomized trials of adjuvant chemotherapy in patients with bladder cancer — coupled with the evidence presented in this study and advances in therapeutic options — will likely increase its prominence in the genitourinary cancer treatment arena, according to Pal and colleagues.
“The data from Galsky and colleagues will likely make the recommendation for adjuvant treatment more emphatic,” Pal and colleagues wrote. “Although cisplatin-based chemotherapy remains the only perioperative standard of care, it is worth noting that alternatives are being explored. In this era of personalized medicine, efforts have been made to target specific molecular subsets of bladder cancer.” – by Cameron Kelsall
Disclosure: Galsky reports travel expenses and intuitional research funding from and/or consultant roles with Astellas Pharma, BioMotiv, Bristol-Myers Squibb, Dendreon, Eli Lilly, Genentech, GlaxoSmithKline, Janssen Oncology, Merck and Novartis. He also reports stock ownership in Dual Therapeutics, as well as a patent held by his employer for technology related to the content of this study. Other study researchers report institutional research funding from Quorum and Sanofi. Pal reports research funding or honoraria from and consultant roles with Astellas Pharma, AVEO Pharmaceuticals, Genentech, Medivation, Myriad Pharmaceuticals and Novartis and Pfizer. Please see the full editorial for a list of the other authors’ relevant financial disclosures.
Perspective
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Elizabeth R. Plimack, MD, MS
The low accrual in previous adjuvant chemotherapy trials have plagued the bladder cancer community for some years. In general, chemotherapy trials are hard to accrue when the chemotherapy is otherwise available, because some doctors wonder why you would randomize a patient in that situation. Even though the trials were not completed, it is likely that doctors had opinions of adjuvant chemotherapy in bladder cancer already and, thus, would either recommend it or not in the real-world setting.Galsky and colleagues deserve credit for conducting a very nice study with publicly available data, and for very carefully controlling the interfering data using propensity scoring. Because these are real-world data, the findings might also have a broader applicability.
The findings were essentially the same as what were seen in the clinical trials — the problem was that the trials did not have enough patients to power the analysis. The retrospective review, however, did.
The best place to give perioperative therapy for bladder cancer is before surgery. But if, for whatever reason, a patient did not receive neoadjuvant chemotherapy or has high-risk pathology, we recommend adjuvant chemotherapy. The report by Galsky and colleagues supports that recommendation.
Perspective
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Derek Raghavan, MD, PhD
I cannot leave unchallenged the opinions of my esteemed colleagues, Drs. Galsky and Plimack. It is always disappointing when bright young clinician investigators, who work very hard and have fine track records, move away from data and support their opinions without hard facts.In their paper on the National Cancer Data Base (NCDB) assessment of adjuvant chemotherapy for invasive bladder cancer, Galsky and colleagues actually make a fine case for the fact that the data do not support routine use of adjuvant cisplatin-based chemotherapy after cystectomy for invasive bladder cancer. The researchers correctly cite all the problems with case-selection bias — including having more robust patients, such as those with insurance, etc — being dominant in the adjuvant chemotherapy group, but fall back on the statistically weak concept of “propensity matching” to make up for the facts. It appears that, in her perspective, Plimack supports their bottom line.
When clinicians consider whether adjuvant chemotherapy should be used routinely in patients with invasive bladder cancer removed by cystectomy, it is wise to remember the following facts:
• No randomized trial has shown a statistically significant survival benefit in a disease that tends to run its course within 5 years; there have been PFS benefits, but that would be expected if the chemotherapy had any beneficial bioimpact;
• The most strongly powered trial (from the EORTC) showed the puzzling result that node-negative cases benefited and node-positive cases did not, suggesting perhaps that adjuvant chemotherapy compensated somewhat for suboptimal surgery. Another explanation is that four cycles of chemotherapy is sufficient to have an impact on node-negative disease but more chemotherapy would be needed to improve survival in node-positive bladder cancer;
• All of the multiple post-hoc analyses and meta-analyses (which, in my opinion, have constituted a huge waste of time) have included at least one trial that was flawed in design and execution (with the cystectomy-only arm dominated by patients who were not offered salvage chemotherapy at the time of relapse); and
• One randomized trial has actually shown inferior OS in association with adjuvant gemcitabine–cisplatin.
Galsky and colleagues’ interpretation of data from the NCDB functionally ignores the potentially huge impact of case and treatment selection bias. Accordingly, it is not appropriate to recommend adjuvant chemotherapy for deeply invasive bladder cancer after cystectomy as representing any type of strong evidence-based guideline.
It is a great shame that our colleagues in genitourinary oncology have refused to test their hypotheses. They had the option when Cora N. Sternberg MD, FACP, and the EORTC offered the correct trial, which was open for accrual in the United States but was poorly supported by folks who assumed they knew the answer to the question … but did not.
Reference:
Sternberg CN, et al. Abstract 4500. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
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