The standard of care for deeply invasive bladder cancer should remain neoadjuvant chemotherapy with MVAC. Adjuvant chemotherapy, with any regimen, remains unproven, with only modestly improved survival trends despite decades of study.
—Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
Treatment of advanced bladder cancer continues to prove challenging, and therapies that offer long-term survival remain elusive. The ASCO Post recently spoke with Derek Raghavan, MD, PhD, FACP, FRACP, FASCO, President of the Levine Cancer Center, Charlotte, North Carolina, about the current state of bladder cancer treatment and what the future clinical picture might look like in this persistently difficult disease.
Next Generation of Inquiry
Immunotherapy is having a renaissance of sorts. Please talk about the role of immunotherapy in bladder cancer.
Bladder cancer is a very interesting disease in that for more than 40 years, we’ve known that immunology is intimately involved in how bladder cancer grows and regresses. In the 1970s, Drs. Paul Lange and Catherine Limas did some elegant studies showing that the prognosis of noninvasive bladder cancer—or what used to be called superficial bladder cancer—was associated with the elaboration of blood group antigens on the surface of the bladder cancer cells.
In the 1980s, Dr. Alvaro Morales and others postulated that you could stimulate the immunity of the mucosa of the bladder to help reject tumor cells. It was found that in noninvasive bladder cancer, administering intravesical bacillus Calmette-Guérin (BCG) would delay tumor recurrence, and some studies suggested that BCG actually improves survival.
As we gained more knowledge, we saw that the ABO blood group determinants were expressed in bladder cancer, and the heavy presence of those substances correlated with a good prognosis. Although we thought that the more favorable prognosis had something to do with the differentiation of the tumor cells, we also realized that it easily could have been produced by an immunologic reaction.
With the passage of time, it became clear that mutations in a number of genes such as RAS and TP53 were associated with different types of bladder cancer. So, when you put this together, it indicates that immunologic function could play an important role in the defense against bladder cancer.
As we fast-forward to the present, we have identified PD-L1 (programmed cell death ligand 1), which puts the brake on T-cell function, and therefore an anti–PD-L1 would release the brake. PD-L1 is expressed heavily in lung cancer, and researchers are looking at a whole series of PD-L1 activations that might stimulate an immune response that would reject lung cancer.
We also know that PD-L1 is heavily expressed in urothelial malignancy, which gives a basis for some immunotherapy trials in invasive and metastatic bladder cancers. Early studies in PD-L1 in bladder cancer that were presented at the 2014 ASCO Annual Meeting were interesting, but they need to be validated.
I certainly see immunotherapy as a promising next generation of inquiry. Although chemotherapy has been a mainstay of treatment for metastatic disease for decades, there have not been major improvements since the development of the MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) and GC (gemcitabine/cisplatin) regimens, so it is time for a new approach.
More Sophisticated Diagnostic Technologies
The diagnosis of bladder cancer has relied on cystoscopy and brush biopsy. Is our ability to evaluate bladder cancer moving forward with the advent of more sophisticated technologies?
Yes. Some years ago, flexible cystoscopy replaced rigid cystoscopy, which was the first important step in moving our diagnostics ahead. Flexible cystography allows a much better view of the whole bladder. Subsequently, we developed the technique of random biopsy, understanding that the changes that beget urothelial carcinoma represent a field effect in the disease.
For instance, you might discover a tumor on the left ureteric orifice, but if you multisite biopsy, you might discover other patches of carcinoma in situ or noninvasive disease. In addition, the flexible cystoscopy can be done as an office procedure and used with the patient under anesthesia to biopsy unique sites. Moreover, we now know that the whole urothelium is at risk, so with flexible cystoscopy, we look at the prostatic urethra and the ureters.
In terms of technologic advances, there’s a new type of fluorescence cystoscopy that uses light to identify mossy patches on the mucosal lining of the bladder, which frequently connotes a tumor site. Another recent advance is narrow-band imaging cystoscopy, in which light of specific blue and green wavelengths is used to enhance the detail of certain aspects of the surface of the mucosa.
Finally, we now have an array of antibody tests that measure antigens released from noninvasive bladder cancers. They come as antibody kits, which allow you to look at gene expression or protein expression, reasoning that the urine is a concentrated soup that could reflect anything sitting in the bladder. This new era of antigen tests is improving the sensitivity and specificity of diagnostic tests.
Adjuvant chemotherapy is standard treatment in breast, colon, and prostate cancers. What is the role of adjuvant chemotherapy in bladder cancer following cystectomy?
There have been myriad trials in this area over the past 20 years. Unfortunately, many of the trials were flawed in their design, being underpowered or having early stopping rules and using disease-free survival instead of overall survival as the endpoint.
If you give any type of adjuvant therapy that works, by definition you have to improve disease-free survival, simply because you’ve dropped the tumor load. And in breast and colon cancers, the results show that overall survival at all time points is statistically better with adjuvant therapy.
Unfortunately, all the bladder cancer trials have a statistically significant increment in progression-free survival and a trend in terms of overall survival, but we don’t know what would have happened, because they all closed too early, had design flaws, or had inadequate powering.
The biggest study was done by the European Organisation for Research and Treatment of Cancer, which was a randomized trial of adjuvant MVAC or GC or high-dose MVAC vs observation after cystectomy for invasive bladder cancer. Unfortunately, the trial closed after years of insufficient accrual. As predicted, because MVAC and GC work in bladder cancer, there was a statistically significant improvement in disease-free survival, but overall survival was seen as just a nonsignificant trend toward improved outcome. The other problem was that the impact was seen in locally extensive tumors without node involvement, suggesting that suboptimal surgery may have been a contributing factor.
‘Slow to Adopt Neoadjuvant Chemotherapy’
Please discuss the role of neoadjuvant chemotherapy in bladder cancer.
There has been a clinically relevant, statistically significant increase in survival from the use of neoadjuvant chemotherapy. Dr. Mark Soloway and I published the first two neoadjuvant single-agent cisplatin trials back in 1984, and we presented the data the next year at the ASCO Annual Meeting.1
The results looked way better than anything we’d seen before, so neoadjuvant chemotherapy was studied in a randomized phase III trial. Although the trial did not show an increment in survival, we found that all the patients had done better.
After looking more deeply into this finding, we realized our neoadjuvant studies were conducted at the time that computed tomography was introduced into routine clinical practice for bladder cancer. Therefore, in our phase II studies, we’d inadvertently ruled out patients who had hitherto undetected abdominal nodal metastases, so, of course, the results were better. That said, there was no survival increment from single-agent cisplatin.
Subsequently, we designed an international randomized trial looking at the CMV (cisplatin/methotrexate/vinblastine) regimen followed by cystectomy or radiotherapy. We wanted to see a 10% survival increment, and in the first trial, we had a 6% increment, so we didn’t meet the requirement; therefore, it was published as a negative study. However, the long-term follow-up showed a statistically significant improvement in outcome.2
Later on in the United States, we showed a median 3-year increase in survival and a 7% increase in cure rate in a Southwest Oncology Group trial. The results were published in The New England Journal of Medicine,3 and it should have been a practice-changing paper, but subsequent reports indicated that the urology community had been very slow to adopt neoadjuvant therapy. However, the urology community is now embracing the use of neoadjuvant chemotherapy with greater frequency.
‘Game-Changer in Surgery’
What surgical advances have increased outcomes for bladder cancer patients?
The original surgical approach was radical cystectomy, which meant excising the bladder and lymph nodes and leaving the patient with an external bag to collect urine. The real game-changer in surgery has been a technique called the Kock Pouch, developed by Dr. Nils Koch and colleagues. The Pouch is an internal vessel into which the ureters drain under the skin of the abdomen, so the patient would be catheterized several times a day. Naturally, not having to walk around with an external plastic bag full of urine markedly improves one’s quality of life.
The next advance was doing a cystectomy with reconstruction, in which the surgeon took bowel tissue and turned it inside out, creating an artificial bladder that could contain urine. The first iteration required a catheter, but later iterations allowed patients to pass urine naturally.
Please share some closing thoughts on the treatment of bladder cancer with the readers.
I think it’s important to note that the neoadjuvant story illustrates the phenomenon of stage migration, which showed that effectively used chemotherapy does alter the natural history in both metastatic and invasive disease. However, it has left us with a conundrum: If it works in neoadjuvant chemotherapy, why not in adjuvant therapy? And this conundrum tells us that we need to put more emphasis in designing better, well-powered studies.
It’s fitting to close by mentioning the development of the MVAC regimen by the late Dr. Alan Yagoda, which was truly practice-changing. The standard of care for deeply invasive bladder cancer should remain neoadjuvant chemotherapy with MVAC, which has been validated in well-powered clinical trials. As mentioned, adjuvant chemotherapy, with any regimen, remains unproven, with only modestly improved survival trends despite decades of study. ■
Disclosure: Dr. Raghavan reported no potential conflicts of interest.
1. Raghavan D, Pearson B, Duval P, et al: Initial intravenous cisplatinum therapy: Improved management for invasive high-risk bladder cancer? J Urol 133:399-402, 1985.
2. Griffiths G, Hall R, Sylvester R, et al: International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: Long-term results of the BA06 30894 trial. J Clin Oncol 29:2171-2177, 2011.
3. Grossman HB, Natale RB, Tangen CM, et al: Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859-866, 2003.