The 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.
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 notthe 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 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 regimenthe 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 diseasewhether indolent or aggressivecould 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(Drug information on mitomycin) (Mutamycin) with maintenance BCG, may be of importance in this regard. Following an initial weekly treatment for 6 weeks with either agent, maintenance 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 recurrencerather 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 advantagebut 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 responsewith reduced toxicityseems like a reasonable path to pursue.
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.
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