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Maintenance Therapy for Superficial Bladder Cancer
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Maintenance Therapy for Superficial Bladder Cancer
Review Article [1] | January 01, 2001
By Michael J. Droller, MD [2]
Transurethral resection remains the standard for first-line treatment of transitional cell carcinoma of
the bladder. This technique clearly defines the pathologic grade and is essential in determining the
clinical stage of
he role of maintenance intravesical chemotherapy or immunotherapy in possibly preventing tumor
recurrence or progression in the urinary bladder is a recurring question that has continued to elude
resolution. Issues of controversy in each case appear to involve study designs that examine
(1) whether maintenance therapy is truly effective, and (2) the choice of the best regimen. However,
other, probably more fundamental, issues also need to be considered. These issues include the
intrinsic biological potential of the various disease forms being treated, mechanism of action of
various agents and regimens upon which rationale for their use may be based, and end points used
to determine treatment efficacy.
T
Of the various trials that have assessed the efficacy of intravesical chemotherapy or immunotherapy
in preventing recurrence (and possibly also progression), most have demonstrated at least
short-term efficacy with intravesical chemotherapy but little long-term benefit for either.
In fact, several multi-institutional studies have reported an overall 7% to 15% benefit with a number
of intravesical chemotherapeutic agents in preventing recurrence (but possibly with less efficacy in
high-grade disease) and little, if any, benefit in preventing progression.
Scrutinizing Results With Intravesical BCG
Risk of progression has pertained largely to high-grade "superficial" disease (or disease of highly
malignant potential). A majority of studies have therefore focused on the use of intravesical bacillus
Calmette-Guérin (BCG) because of its apparent efficacy in carcinoma in situ. Although intravesical
BCG has become the standard of treatment for flat carcinoma in situ, and more recently, for
high-grade transitional cell cancer that invades the lamina propria, closer scrutiny, particularly in
longer-term studies, indicates that the efficacy of BCG in preventing both recurrence and
progression may be less impressive than initial reports suggested.
For example, original reports described a 50% to 70% therapeutic efficacy with a single 6-week
induction course of BCG in the elimination of flat carcinoma in situ; an additional 50% of initial
failures could apparently be salvaged by a second 6-week course. However, one-third of patients
who failed a second course were found to have metastatic disease at the time of surgical
exploration. Moreover, a long-term review of the same patients who were initially thought to be
therapeutic "successes" found development of metastatic disease in one-third of patients and the
need for cystectomy in an additional one-third.
These results suggest several possible interpretations. For one, the variable outcomes may reflect
the likelihood that a heterogeneous group of tumors comprised what was initially described as
homogeneous for stage and grade. Thus, some tumors appeared to be responsive to BCG and others
did not—the latter possibly expressing their potential for more aggressive behavior.
Alternatively, methods that were initially used to detect disease may not have been sufficiently
sensitive, or regimens that were used may not have been sufficiently effective to maintain an initial
response. Thus, patients whose tumors responded initially might have maintained their response
with continued treatment if patients who were early failures (as expressed by progressive disease)
were excluded.
Moreover, several studies have demonstrated that certain molecular aspects of a tumor may
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Maintenance Therapy for Superficial Bladder Cancer
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indicate a greater intrinsic aggressiveness. Some of these tumors may also be intrinsically more
resistant to intravesical treatments and may require earlier cystectomy if they fail to respond to
intravesical therapy both promptly and completely.
Selecting the ‘Best’ Regimen
The specific therapeutic regimen may also determine efficacy. When considering intravesical
chemotherapy, for example, increased dosage, prolongation and/or repetitiveness of exposure, and
precise delivery of an active agent to chemosensitive cells would be important parameters to
consider.
Several studies have begun to address these issues by characterizing conditions that may be
necessary to optimize clinical efficacy. These conditions are likely to be quite different for biological
response modifiers (eg, BCG, interferon) as immunotherapeutic agents. With these agents, increased
dosage may actually compromise further recruitment of an effective immune response and may be
suppressive once an optimum dose/efficacy has been exceeded. On the other hand, the rationale for
a "booster" treatment at the appropriate interval may effectively enhance leukokine production and
thereby further therapeutic benefit.
Questions remain as to (1) why certain tumors do not respond to an induced immune response, and
(2) whether this reflects characteristics of the tumor itself or the actual ability to invoke and then
boost an effective immune response. Recent studies purporting to demonstrate the efficacy of a
booster BCG regimen—the so-called 6 + 3 protocol, as referenced in the article by Baselli and
Greenberg[1,2]—do not definitively answer these questions.
Interpretation of Outcomes
In these studies, patients with superficial bladder cancer (but predominantly with carcinoma in situ)
treated with a 6-week intravesical BCG induction course were randomized to receive no additional
treatment or an additional 3-week booster instillation course after 6 weeks. Control patients
experienced a median recurrence-free survival of 35.7 months, compared to 76.8 months for those
who did receive the maintenance or booster treatment. Estimated median time to progression in the
untreated group was 111.5 months, while numbers in the maintenance group were insufficient to
permit comparable estimations.
In these control and maintenance groups (comprised of patients with carcinoma in situ and/or rapidly
recurring stages Ta or T1 disease), the complete response rates to the initial 6-week induction
course of BCG were 87% and 83%, respectively. This seems inordinately high and could imply that
some patients did not have particularly aggressive tumors, either in terms of recurrence or
progression. This possibility is also suggested by the lengthy recurrence-free survival (median: 35.7
months) and the nearly 10-year median time to progression in the nonbooster group.
Thus, the intrinsic biology of disease—whether indolent or aggressive—could have played a decisive
role in outcomes. Correspondingly, this same biological potential could explain the eventual
recurrence of disease even in the booster-treated group, as suggested by the ultimate median
recurrence in these patients of 76.8 months.
Also somewhat problematic in the interpretation of outcomes is the issue of treatment compliance. A
majority of patients in the maintenance (booster) group actually failed to comply with the full
regimen of planned treatment, demonstrating only a 16% completion rate (39 of 243 patients). The
purported advantage of maintenance therapy in prolonging disease-free recurrence and preventing
progression seems difficult to assess if the majority of patients did not actually receive the
prescribed treatment regimen. Conceivably, lengthy maintenance therapy may not ultimately be
necessary; only initial boosting may be needed for treatment efficacy. However, patient selection
might also have played a role in the obtained results.
Findings from studies conducted by the Swedish-Norwegian Bladder Cancer Study Group, which
compared maintenance mitomycin (Mutamycin) with maintenance BCG, may be of importance in this
regard.[3] Following an initial weekly treatment for 6 weeks with either agent, maintenance
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Maintenance Therapy for Superficial Bladder Cancer
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treatment consisted of monthly instillations for 1 year and then every 3 months the following year.
No difference in progression rates was detected between the two groups (approximately 19%
each)—rates of progression were highest for stage T1 disease and grade 3 disease. Tumor recurrence
decreased in the BCG-treated group, and this translated into an improved disease-free survival.
Effect of End Point Selection
In such studies, the selection of end points for analysis may be important in considering the
interpretation of ultimate treatment efficacy. Disease-free survival only indicates the absence of
detectable recurrence. Conceivably, this may reflect sensitivity of the methodology used to detect
recurrence—rather than the ultimate efficacy of treatment.
Attempts to visualize disease endoscopically may not detect changes in various "fields" of the
urothelium if they have not yet been phenotypically expressed. Moreover, cells that have undergone
neoplastic transformation may not be detectable by urinary cytology, either because of failure to
recognize cells as cytologically malignant or failure to obtain cells that are sufficient for visual
analysis. On the other hand, absence of detectable disease may be an advantage—but only if it can
be safely assumed that any undetectable abnormal cells will not express aggressive behavior while
they remain either unrecognized or unresponsive to maintenance treatments.
BCG has become the standard in treating high-risk superficial urothelial cancer. However,
observations that substantial numbers of tumors may not fully respond to such therapy indicate the
need to further delineate effective regimens. In addition, individual neoplasms need to be
characterized in ways that may determine both their responsiveness to particular treatments and
the likelihood of their recurrence and progression.
The role of BCG in treating low-risk disease should be considered with caution, since its potential
toxicity may outweigh potential benefit. If recruitment of an immune response is indeed responsible
for BCG efficacy, finding other means to recruit this response—with reduced toxicity—seems like a
reasonable path to pursue.
Conclusions
Taken together, numerous advances have been made in our approach to the treatment of different
forms of superficial urothelial cancers. We now have earlier diagnoses of disease, the recognition of
potentially aggressive tumor diatheses on the basis of their molecular characteristics and phenotypic
expression, and an understanding that different pathways of tumor development may reflect or
represent varying biologic potentials. Each of these factors has contributed to an improved
assessment of the type of tumor diathesis that may be present and the requirement for a particular
type of treatment approach.
However, we still need a more precise means of characterizing the biological potential of an
individual tumor diathesis. We also need intravesical agents and regimens that can be employed
most effectively in preventing recurrence and progression. The accuracy of end points in interpreting
results is contingent upon our understanding of a disease, both at its initial presentation and in its
ultimate capabilities. Efficacies of various treatments need to be studied in this context, and
interpretation of outcomes need to be based on appropriate experimental designs, as well as the
acquisition of meaningful end point data.
Suggested Readings
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Herr HW: Tumor progression and survival of patients with high grade, noninvasive papillary (TaG3)
bladder tumors: 15-year outcome. J Urol 163(1):60-61; discussion 61-62, 2000.
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Maintenance Therapy for Superficial Bladder Cancer
Published on Psychiatric Times
(http://www.psychiatrictimes.com)
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immunotherapy for recurrent Ta, T1 and carcinoma in situ transitional cell carcinoma of the bladder:
A randomized Southwest Oncology Group Study. J Urol 163:1124-1129, 2000.
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Links:
[1] http://www.psychiatrictimes.com/review-article
[2] http://www.psychiatrictimes.com/authors/michael-j-droller-md
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