Ask the Doctor
For this issue we thank Michael O’Donnell, MD, FACS, Holden Cancer Center, University of Iowa Hospital, for answering our questions.
Q. Please explain how the FISH test works. Which patients would benefit from its use? Should it be given as a matter of routine? If so, in addition to cytology and/or cystoscopy or should it stand on its own?
A. FISH stands for Fluorescent In Situ Hybridization. It is a technique that uses colored DNA probes to count the number of certain chromosomes or specific chromosomal regions in individual cells derived from the bladder lining. The thought is that cancer cells go haywire as they start growing aggressively and as a result start making major mistakes in replicating their chromosomes and DNA.
The final FISH result comes out as NORMAL, ABNORMAL, or INCONCLUSIVE and is based on meeting predetermined thresholds for the number of abnormalities seen. Inconclusive tests occur when there are insufficient total cells for analysis, contamination, or abnormal results right on the borderline.
As with many new tests, the first results that came out with FISH tended to over exaggerate its performance. Initially it was reported that FISH tests picked up over 85% of all bladder cancers (sensitivity of over 85%) and was fairly accurate in its results (specificity of 96%). More recent “real world” reports, however, suggest sensitivity closer to 75% and a specificity in the 70-80% range. The practical result of these performance characteristics is that a normal (or negative) FISH test does not rule out cancer. Similarly, an abnormal (or positive) FISH does not mean someone has cancer. As a comparison, a positive cytology test for high grade cancer is right about 95% of the time. The problems with cytology are that it is highly dependent on how good the pathologist is. Cytology still fails to detect over 50% of all bladder cancers.
Does that mean that the FISH test is worthless? No, it means that the LIKLIHOOD of cancer is increased or decreased by an abnormal or normal FISH test, respectively. As such, the FISH test cannot be used in isolation but rather should be used in the context of all the other clinical data including the results of cystoscopy and cytology.
Another vexing issue with an abnormal FISH test is that it may “anticipate” the recurrence of bladder cancer by many months before a tumor can be found. This has been referred to as an “anticipatory positive” FISH. Unfortunately, areas in the bladder that have been subject to years of carcinogen exposure (e.g. from smoking) may already have abnormal chromosome signatures yet are still insufficient to be true cancer. This is commonly referred to as dysplasia. This would explain why many patients with abnormal FISH tests still don’t have cancer but remain at higher risk to eventually develop it.
Since the FISH test is still so new, many urologists have not figured out just how to incorporate it into their practices. Also, the FISH test is quite expensive (often more than $500 per test) so it should not be used haphazardly.
Q. What are the treatment alternatives for a bladder cancer patient who does not respond to BCG?
A. With bladder cancer treatment, the devil is always in the details. Patients may “fail” BCG in many different ways, the exact circumstances of which help determine the best next course of action. Patients may have recurrent cancer at the first post-treatment cystoscopy/cytology or they may relapse at a much later date. They may fail one 6-week course, more than one course, or while on active maintenance therapy. They may fail with low-grade disease or high-grade disease. Patients may also fail simply because they cannot tolerate the BCG at the current treatment regimen. However, despite all these nuances, there are several general guidelines for subsequent therapy:
(1) Any patient with high-grade disease, especially invasive stage T1 or CIS, who shows actual worsening of disease in stage, grade or extent while on BCG therapy should be considered for radical therapy early (i.e. cystectomy). This usually signifies a very aggressive subtype of bladder cancer. If medically unfit, alternative treatment (discussed below) can be considered.
(2) Any patient with high-grade disease who fails two back-toback courses of BCG should also be strongly considered for cystectomy.
(3) Most patients who show some progress with the first course of BCG should be re-treated with another course of BCG as up to half will obtain a complete response. Higher risk patients with high grade stage T1 or CIS should especially consider the addition of the immune augmenting agent interferon with the next course of BCG. A second course of BCG can be dose reduced to 1/2 or 1/3rd of usual dose, improving its tolerability.
(4) Patients relapsing after one course of BCG without stage or grade progression are also good candidates for more BCG with or without interferon. Patients relapsing after two or more prior courses of BCG should only be considered for retreatment (recommend BCG with interferon) if the timing between relapses is one year or greater.
(5) Patients relapsing or failing BCG with low volume, noninvasive, low grade papillary bladder cancer rarely need to come to cystectomy at the next step and should be considered for alternative treatments.
(6) Patients felt to be intolerant to BCG can often be helped by substantially lowering the BCG dose (to 1/3 or 1/10th), spreading out the treatments 2 weeks apart, reducing the dwell time to as little as 30 minutes, or providing fluoroquinolone antibiotics 6 and 18 hours after each treatment.
(7) In general, single agent conventional intravesical chemotherapy (mitomycin, thiotepa, adriamycin) is ineffective after BCG failure with less than 20% long term disease free rate.
(8) Newer intravesical chemotherapy agents such as gemcitabine or docetaxel are showing activity in patients previously failing BCG, especially in the form of combination sequenced therapy, e.g. gemcitabine X 1.5 hours followed immediately by mitomycin X 2 hours. However, these strategies remain investigational at present and are not yet considered standard therapy. Consult a specialist urologist in this field before considering them.
(9) Patients with high grade, stage T1 or CIS wishing to retain their bladders after 2 or more failures of a BCG program need to realize that there is a proportionately increased risk of progression to potentially lethal disease with further delay. There is no completely safe window during the time investigational therapy is being tried. The risks of progression per 3-month quarter may be up to 5% with each 3-month delay.
Q. Why does bladder cancer have such a high recurrence rate?
A. Superficial (non muscle-invasive) bladder cancer does have one of the highest recurrence rates of any solid cancer, upwards of 70% within 5 years. There are at least 4 reasons responsible for this high rate of recurrence:
(1) Not all tumors are found during the planned conventional white light cystoscopy and resection (TURB). An additional 20% are seen under blue-light cystoscopy using an enhancing dye placed into the bladder beforehand. This technique is currently under investigation for FDA approval in the U.S. Also, for more invasive stage T1 tumors there is a 30% or higher chance of missing true muscle invasion and a greater than 50% of leaving residual cancer behind. For this reason it is recommended that most stage T1 tumors be re-TURB’d within 4-6 weeks.
(2) Tumors may re-implant after TURB. Like dandelion seeds they may re-attach to new areas and start new tumors. The most effective way to prevent this is for the urologist to administer a chemotherapy drug like mitomycin into the bladder within 6 hours of every TURB.
(3) Intravesical drugs such as chemotherapy or BCG may fail to eliminate microscopic focuses of cancer that are too small to be seen. Higher concentrations of chemotherapy drugs (same dose in smaller volume) and minimizing dilution, newer drugs, and combination strategies may help this.
(4) The diseased bladder from years of carcinogen exposure may let brand new cancers emerge over the course of time. Maintaining a healthy lifestyle including quitting smoking remains an important first step patients may take in reducing recurrence. There is also some evidence that high dose antioxidant vitamins will assist in this regard. A true chemopreventative drug, however, has not yet been found.
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