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Bladder cancer: Defining the clinical problem
Bladder Cancer: Defining The Clinical Problem Willet F. Whitmore, Jr., M.D. From the Urologic Service, Memorial Sloan-Kettering Cancer Center, New York, New York
Only forty years ago, it was not uncommon to hear bladder cancer characterized as the blackest page in urology. Some might argue that it remains so, but few, I think, would deny that important progress has been made in our understanding of virtually all aspects of this disease. A historical review of that progress, terminating with the current status of knowledge relative to etiology, tumor characterization, diagnosis, staging, and treatment, would provide a clear perspective of the advances that have already occurred. However, I have chosen to use the current state-of-the-art, perceived through my own biases, as the background against which some of the principal persisting problems and pot ential solutions may be highlighted. The latter will be the major subjects of discussion and may be expected to illustrate .the common scientific experience that attempted solution of one problem may generate others. Cancer Biology Although it is appropriate to state that the longterm goal is prevention of bladder cancer, it would be an exaggeration to imply that this solution to the problem is on the horizon. Clinical and laboratory investigations indicate that the process of bladder carcinogenesis is a multi-stage one involving a variety of potential initiators and promoters and that the latent period before recognized tumor presentation is long. Such considerations complicate understanding of etiology and prevention and make credible the possibility of variations in the causes of bladder cancer from place to place and from time to time. Furthermore, these considerations, together with the increasingly well-documented morphologic and biologic heterogeneity of bladder tumors, leave open the possibility that such heterogeneity may stem from correspondingly different causes. Within the past year, discoveries in molecular genetics, notably studies utilizing recombinant DNA technology, have led to the recognition of proto-oncogenes as DNA sequences of apparently normal cells capable
<,U l' r LE:lIENT TO APRIL
I
VOLU~IE
XXIII, NmlBER 4
of inducing rapid oncogenic transformation under appropriate conditions. These observations have provided evidence of an alteration of the genome associated with the evolution of some cancers. How and whether all of these considerations may be reconciled into a potentially unifying concept of carcinogenesis remain to be defined. Tumor Characterization Although the tumor phenotype and natural history must be a consequence of host-tumor interaction , no host features which are clinically useful correlates of such features have been identified. Tumors have been characterized on the basis of size, number, gross morphology (papillary or solid), location, grade, character of infiltration, blood vessel invasion, lymphatic invasion, cell type, T, N, and 1\1 categorizations, certain biochemical characteristics, immunologic features, electron microscopic appearances, tumor associated mucosal abnormalities, etc .. Such features have different utility in the taxonomical classification of bladder tumors and, to varying degrees, have correlated with biologic behavior as well . In the face of the practical inability to factor all such characteristics into either a taxonomical or behavioral classification, the four features of grade, location, polychronotopism, and stage have been and remain the most simple, available, costeffective, and practically useful features of tumor characterization. Such limited characterization has, however, a. number of obvious weaknesses, including: 1) the subjectivity in interpretation of grade; 2) the various limitations in accurate T, N, and M categorizations; 3) omission in reports of potentially important considerations such as tumor size, blood vessel or . lymphatic invasion, etc.; 4) the more fundamental criticism that such . characterization represents a crude "laundry list" of tumor morphologic features which may parallel, but which provide no real insights into , tumor biology. One can't judge a book by its cover, yet, that is essentially what one tries to do.
5
Solutions of such problems rest with refinements and nuances in means for tumor characterization which will provide more reliable insights into tumor behavior than are achieved with current methods. It may indeed be argued that such will provide only a more sophisticated "laundry list" of tumor properties than already exists, but if it serves the purpose, progress will have been made.
ing, however, are the possibilities of improved staging offered by the development of transurethral ultrasonography for T categorization and of nuclear magnetic resonance scanning for T, N, and M categorization. Lymphoscintigraphy and/or lymphangiography supplemented with fine needle biopsy remain to be more extensively investigated, although there is evidence of their utility in N categorization.
Diagnosis and Staging Once a bladder tumor is suspected, cystoscopy and biopsy are standard and reliable methods of establishing a diagnosis. Urinary cytology and flow cytometry have proved useful supplements to cystoscopy and biopsy in the diagnosis and follow-up of patients with bladder tumors and have also been useful in monitoring the effects of treatment. However, the facilities for such examinations remain suboptimal. Approximately one-fourth of patients with bladder tumors develop muscle infiltrating lesions, the majority presenting without antecedent history of recognized T~, Tis or T 1 lesions. This suggests the need for a screening test to permit earlier detection of such patients. There is evidence to indicate that urine cytology might be useful in identifying patients with such tumors at an earlier T category. However, it would be mandatory to identify the high risk groups in whom such detection techniques would be cost-effective, an exercise dependent upon the continued efforts of epidemiologists. One wonders whether the risk ratios for already identified bladder tumor etiologic factors are appreciably different among patients presenting with muscle infiltrating tumors than among those presenting with T., r; or T 1 lesions. Not all patients with positive cytology or positive flow cytometry have cystoscopically evident lesions, and the use of chromocystoscopy with either conventional or ultraviolet light illumination to distinguish differential uptake of a variety of chromophores in tumorous vs. non-tumorous mucosa is being investigated as a potentially useful adjunct to conventional cystoscopy. Problems in tumor characterization have already been mentioned. Although the best of current tumor characterizations may be considered incomplete in terms of specifying all potentially important recognized variables, uniformity and completeness of tumor characterization within reasonable guidelines are being repeatedly emphasized and continually improved through the efforts of national (American Joint Committee) and international (WHO) groups. Quite apart from the optimal utilization and standardization of available techniques of clinical stag-
Treatment of T., Tis> T 1 Lesions About 70 % of patients with bladder tumors present with T., Tis' or Tj lesions. Such may include both low-grade and high-grade papillary neoplasms and flat carcinoma in situ. Clinical experience has indicated that the resectoscope offers focal control of such lesions with an effectiveness analogous to that of local excision of skin cancers. Thus, endoscopic surgery for bladder tumors has become a highly useful and acceptable technique, especially since the morbidity and mortality are low and the surgery can be repeated almost ad infinitum with essentially no associated functional sacrifices. Such treatment does not obviate the possibility of new tumor "occurrences" in bladder, urethra, or upper tracts, and the possibility that such treatment may even foster "bladder occurrences" exists. Apart from polychronotopism, the principal problems are clinical errors in T categorization (principally in accurately determining depth of muscle infiltration), the occurrence of prostatic urethral and/or ureteral tumors, and the subsequent development of muscle infiltrating tumors in patients treated successfully for superficial lesions. Treatment and prophylaxis of polychronotopism have involved the systemic use of biologic response modifiers such as 13-cis-retinoic acid, intravesical treatment with cytotoxic drugs or BCG, or systemic administration of biologic response modifiers (vitamin Be) or of cytotoxic agents. Standardization of techniques for patient selection for treatment and for assessment of response remains a problem and contributes to the confusion of clinical reports relative to the efficacy of various regimens. The occurrence of prostatic urethral and terminal ureteral tumors in patients apparently successfully treated for flat, multifocal carcinoma in situ of the bladder by intravesical therapy is consistent with both the natural history of the disease and with a purely local "contact" effect of such treatment and indicates the need for a systemic form of management in such patients. The identification of a muscle infiltrating tumor upon the follow-up evaluation of a patient previously treated "successfully" for Tis or T 1 bladder tumors is a recognized but nevertheless disconcert-
G
SUPPLDIENT TO APRIL
I
VOLUME XXIII,
NU~IBER
4
ing event. Efforts to relate prior tumor number, size, grade, associated mucosal abnormalities, ABH antigen deletion, aneuploidy, chromosome karyotype, etc. to such tumor progression have demonstrated significant correlations, but these have not been sufficiently predictive to constitute a basis for a categorical radical treatment recommendation in the individual patient. Other means for characterizing tumors are needed and will require correlations with other recognized tumor features, with tumor natural history, and with tumor response to therapy. More sensitive and specific indicators of relevant features of tumor heterogeneity will hopefully emerge as "predictors." Treatment of T 2 , T 3 , T 4 Lesions Approximately 20 % of patients with bladder tumors demonstrate muscle infiltration at initial presentation. Experience has generally indicated that a 40-60 % five-year- survival rate following effective local treatment represents the upper limit of curability in such patients, with regional lymph node andl or distant metastases accounting for the failures. Local control with minimal morbidity, mortality, and functional sacrifice remains one goal, and both radiation therapy and surgery have contributed to this objective, surgery more convincingly than irradiation. Tumor grade, site, multicentricity, and T category have usually been the important considerations in decisions regarding therapy. The T category remains the least assuredly defined of these variables. Refinements in technology for T categorization will be awaited with particular interest since the decision relative to endoscopic versus more aggressive methods for local control is so dependent upon such characterization. For lesions unsuitable for local control by conservative treatment, the important need is to be able to select from the various treatment options-irradiation, radical excision (partial vs. total cystectomy), or integrated irradiation with surgery-those which offer the greatest possibility of local control and the least associated functional sacrifice. Once a therapeutic regimen has been selected, however, an accurate prediction of tumor response is difficult to make. This point is readily demonstrated by the variable response to irradiation of tumors which appear similar by light microscopy and other currently utilized features of tumor characterization. The high failure rate from distant metastases within two years of treatment in patients with muscle infiltrating tumors is probably largely a consequence of preexisting metastases unrecognized by current techniques of M categorization. This population of patients might be spared the burden of ag-
Sl!PI'LE~I'IE1'\T
TO APRIL
I
VOLmlE XXIII, NmlBER 4
gressive local treatment if the systemic nature of their disease could be reliably determined before local treatment was started. The occasional therapeutic effectiveness of definitive irradiation and the technical feasibility of "salvage" cystectomy have lent substance to the argument that patients requiring radical treatment for bladder cancer might first be given definitive irradiation with the hope that such treatment would control the cancer and conserve bladder function, but with the realization that if such treatment failed, salvage cystectomy might still be curative. Such an empiric approach emphasizes the need for criteria for predicting radioresponsiveness. Evidence that irradiation may result in rapid disappearance of aneuploid stem cell lines from bladder washings in patients with muscleinfiltrating bladder cancers suggests the possible usefulness of flow cytometry in detecting radioresponsiveness. This finding provides evidence of the therapeutic response heterogeneity of apparently similar bladder tumors. In spite of the low morbidity and mortality of radical cystectomy, it is a major procedure with devastating impacts on the quality if not the quantity of life. Patients "cope" well with the procedure, but this is more a tribute to the human spirit than to surgical skill. Continued efforts to diminish the adverse effects of the procedure on urinary and sexual functions are warranted. Endoscopic applications of laser technology offer potential prospects of local control of T 2 and T 3 tumors and may demonstrate advantages over conventional endoscopic procedures in the control of superficial tumors. Such treatment has been experimentally demonstrated to be capable of producing a controlled coagulation necrosis of the full thickness of bladder wall without subsequent perforation. The use of radiosensitizers or of chemotherapy in conjunction with irradiation for improving radioresponsiveness is another promising area for investigation. Metastatic Tumors (N + and lor M + ) Approximately 5% of patients present with metastatic bladder neoplasm, and approximately half of patients with apparently localized muscleinfiltrating tumors develop evidence of distant metastases within two years. Surgery and irradiation are of limited usefulness in the palliation or cure of metastatic tumors, in contrast to their major roles in local tumor control. The control of metastatic disease continues to depend principally upon either its prevention by earlier diagnosis and effective treatment of local disease or its eradication by systemic therapy. The early appearance of distant metastases
7
in patients treated by cystectomy for bladder cancer provides compelling circumstantial evidence that such individuals harbored occult metastatic disease prior to cystectomy. For patients with metastatic disease in the regional nodes, the prospects of surgical cure or possibly radiation cure, even in the face of limited nodal metastases, are generally in the 10-20 % range. For these and other high risk patients, programs of adjuvant chemotherapy using agents of defined activity are under exploration. An important question is whether any of the current generation of drugs produces high enough complete response rates in patients with advanced measurable disease to render them capable of destroying micrometastases. Perhaps the most that can be expected from the application of adjuvant chemotherapy with the current generation of cytotoxic agents is prolongation of disease free intervals. A further question is whether "adjuvant" treatment of occult metastases offers a survival advantage over treatment of overt recurrence. Randomized clinical trials will help to answer these questions. Phase II studies have defined the activity of a number of single agents against advanced measurable bladder cancer, and Phase III studies designed to compare the effectiveness of various agents, alone or in combination, are in progress. Experimental systems for selecting drugs for the treatment of patients with bladder cancer remain an important con-
8
sideration, and the induction or transplantation of bladder tumors in experimental animals, the clonogenic assayof human tumors in soft agar, and the study of human tumors grown in the nude mouse are test systems currently under investigation. The designation "bladder neoplasm" clearly encompasses a morphologically and biologically heterogeneous group of tumors with various natural histories and with various responses to the same or to different treatments. Although this diversity may ultimately be correlated with definable differences amongst such tumors, morphologic or otherwise, information. is currently insufficient to permit more than gross and tentative distinctions between groups. Apparently similar (morphologically). tumors are treated more or less uniformly, yet may respond differently. Comment Mark Twain characterized the optimist as one who defines the glass as half full in contrast to the pessimist who sees it as half empty, and it would not be amiss to characterize the bladder tumor picture as dark with problems, yet bright with prospects for solutions.
Urologic Service Memorial Sloan-Kettering Cancer Center New York, New York 10021
SUPPLEME1':T TO APRIL
I
VOLUME XXIII, Nm.mER 4
Only forty years ago, it was not uncommon to hear bladder cancer characterized as the blackest page in urology. Some might argue that it remains so, but few, I think, would deny that important progress has been made in our understanding of virtually all aspects of this disease. A historical review of that progress, terminating with the current status of knowledge relative to etiology, tumor characterization, diagnosis, staging, and treatment, would provide a clear perspective of the advances that have already occurred. However, I have chosen to use the current state-of-the-art, perceived through my own biases, as the background against which some of the principal persisting problems and pot ential solutions may be highlighted. The latter will be the major subjects of discussion and may be expected to illustrate .the common scientific experience that attempted solution of one problem may generate others. Cancer Biology Although it is appropriate to state that the longterm goal is prevention of bladder cancer, it would be an exaggeration to imply that this solution to the problem is on the horizon. Clinical and laboratory investigations indicate that the process of bladder carcinogenesis is a multi-stage one involving a variety of potential initiators and promoters and that the latent period before recognized tumor presentation is long. Such considerations complicate understanding of etiology and prevention and make credible the possibility of variations in the causes of bladder cancer from place to place and from time to time. Furthermore, these considerations, together with the increasingly well-documented morphologic and biologic heterogeneity of bladder tumors, leave open the possibility that such heterogeneity may stem from correspondingly different causes. Within the past year, discoveries in molecular genetics, notably studies utilizing recombinant DNA technology, have led to the recognition of proto-oncogenes as DNA sequences of apparently normal cells capable
<,U l' r LE:lIENT TO APRIL
I
VOLU~IE
XXIII, NmlBER 4
of inducing rapid oncogenic transformation under appropriate conditions. These observations have provided evidence of an alteration of the genome associated with the evolution of some cancers. How and whether all of these considerations may be reconciled into a potentially unifying concept of carcinogenesis remain to be defined. Tumor Characterization Although the tumor phenotype and natural history must be a consequence of host-tumor interaction , no host features which are clinically useful correlates of such features have been identified. Tumors have been characterized on the basis of size, number, gross morphology (papillary or solid), location, grade, character of infiltration, blood vessel invasion, lymphatic invasion, cell type, T, N, and 1\1 categorizations, certain biochemical characteristics, immunologic features, electron microscopic appearances, tumor associated mucosal abnormalities, etc .. Such features have different utility in the taxonomical classification of bladder tumors and, to varying degrees, have correlated with biologic behavior as well . In the face of the practical inability to factor all such characteristics into either a taxonomical or behavioral classification, the four features of grade, location, polychronotopism, and stage have been and remain the most simple, available, costeffective, and practically useful features of tumor characterization. Such limited characterization has, however, a. number of obvious weaknesses, including: 1) the subjectivity in interpretation of grade; 2) the various limitations in accurate T, N, and M categorizations; 3) omission in reports of potentially important considerations such as tumor size, blood vessel or . lymphatic invasion, etc.; 4) the more fundamental criticism that such . characterization represents a crude "laundry list" of tumor morphologic features which may parallel, but which provide no real insights into , tumor biology. One can't judge a book by its cover, yet, that is essentially what one tries to do.
5
Solutions of such problems rest with refinements and nuances in means for tumor characterization which will provide more reliable insights into tumor behavior than are achieved with current methods. It may indeed be argued that such will provide only a more sophisticated "laundry list" of tumor properties than already exists, but if it serves the purpose, progress will have been made.
ing, however, are the possibilities of improved staging offered by the development of transurethral ultrasonography for T categorization and of nuclear magnetic resonance scanning for T, N, and M categorization. Lymphoscintigraphy and/or lymphangiography supplemented with fine needle biopsy remain to be more extensively investigated, although there is evidence of their utility in N categorization.
Diagnosis and Staging Once a bladder tumor is suspected, cystoscopy and biopsy are standard and reliable methods of establishing a diagnosis. Urinary cytology and flow cytometry have proved useful supplements to cystoscopy and biopsy in the diagnosis and follow-up of patients with bladder tumors and have also been useful in monitoring the effects of treatment. However, the facilities for such examinations remain suboptimal. Approximately one-fourth of patients with bladder tumors develop muscle infiltrating lesions, the majority presenting without antecedent history of recognized T~, Tis or T 1 lesions. This suggests the need for a screening test to permit earlier detection of such patients. There is evidence to indicate that urine cytology might be useful in identifying patients with such tumors at an earlier T category. However, it would be mandatory to identify the high risk groups in whom such detection techniques would be cost-effective, an exercise dependent upon the continued efforts of epidemiologists. One wonders whether the risk ratios for already identified bladder tumor etiologic factors are appreciably different among patients presenting with muscle infiltrating tumors than among those presenting with T., r; or T 1 lesions. Not all patients with positive cytology or positive flow cytometry have cystoscopically evident lesions, and the use of chromocystoscopy with either conventional or ultraviolet light illumination to distinguish differential uptake of a variety of chromophores in tumorous vs. non-tumorous mucosa is being investigated as a potentially useful adjunct to conventional cystoscopy. Problems in tumor characterization have already been mentioned. Although the best of current tumor characterizations may be considered incomplete in terms of specifying all potentially important recognized variables, uniformity and completeness of tumor characterization within reasonable guidelines are being repeatedly emphasized and continually improved through the efforts of national (American Joint Committee) and international (WHO) groups. Quite apart from the optimal utilization and standardization of available techniques of clinical stag-
Treatment of T., Tis> T 1 Lesions About 70 % of patients with bladder tumors present with T., Tis' or Tj lesions. Such may include both low-grade and high-grade papillary neoplasms and flat carcinoma in situ. Clinical experience has indicated that the resectoscope offers focal control of such lesions with an effectiveness analogous to that of local excision of skin cancers. Thus, endoscopic surgery for bladder tumors has become a highly useful and acceptable technique, especially since the morbidity and mortality are low and the surgery can be repeated almost ad infinitum with essentially no associated functional sacrifices. Such treatment does not obviate the possibility of new tumor "occurrences" in bladder, urethra, or upper tracts, and the possibility that such treatment may even foster "bladder occurrences" exists. Apart from polychronotopism, the principal problems are clinical errors in T categorization (principally in accurately determining depth of muscle infiltration), the occurrence of prostatic urethral and/or ureteral tumors, and the subsequent development of muscle infiltrating tumors in patients treated successfully for superficial lesions. Treatment and prophylaxis of polychronotopism have involved the systemic use of biologic response modifiers such as 13-cis-retinoic acid, intravesical treatment with cytotoxic drugs or BCG, or systemic administration of biologic response modifiers (vitamin Be) or of cytotoxic agents. Standardization of techniques for patient selection for treatment and for assessment of response remains a problem and contributes to the confusion of clinical reports relative to the efficacy of various regimens. The occurrence of prostatic urethral and terminal ureteral tumors in patients apparently successfully treated for flat, multifocal carcinoma in situ of the bladder by intravesical therapy is consistent with both the natural history of the disease and with a purely local "contact" effect of such treatment and indicates the need for a systemic form of management in such patients. The identification of a muscle infiltrating tumor upon the follow-up evaluation of a patient previously treated "successfully" for Tis or T 1 bladder tumors is a recognized but nevertheless disconcert-
G
SUPPLDIENT TO APRIL
I
VOLUME XXIII,
NU~IBER
4
ing event. Efforts to relate prior tumor number, size, grade, associated mucosal abnormalities, ABH antigen deletion, aneuploidy, chromosome karyotype, etc. to such tumor progression have demonstrated significant correlations, but these have not been sufficiently predictive to constitute a basis for a categorical radical treatment recommendation in the individual patient. Other means for characterizing tumors are needed and will require correlations with other recognized tumor features, with tumor natural history, and with tumor response to therapy. More sensitive and specific indicators of relevant features of tumor heterogeneity will hopefully emerge as "predictors." Treatment of T 2 , T 3 , T 4 Lesions Approximately 20 % of patients with bladder tumors demonstrate muscle infiltration at initial presentation. Experience has generally indicated that a 40-60 % five-year- survival rate following effective local treatment represents the upper limit of curability in such patients, with regional lymph node andl or distant metastases accounting for the failures. Local control with minimal morbidity, mortality, and functional sacrifice remains one goal, and both radiation therapy and surgery have contributed to this objective, surgery more convincingly than irradiation. Tumor grade, site, multicentricity, and T category have usually been the important considerations in decisions regarding therapy. The T category remains the least assuredly defined of these variables. Refinements in technology for T categorization will be awaited with particular interest since the decision relative to endoscopic versus more aggressive methods for local control is so dependent upon such characterization. For lesions unsuitable for local control by conservative treatment, the important need is to be able to select from the various treatment options-irradiation, radical excision (partial vs. total cystectomy), or integrated irradiation with surgery-those which offer the greatest possibility of local control and the least associated functional sacrifice. Once a therapeutic regimen has been selected, however, an accurate prediction of tumor response is difficult to make. This point is readily demonstrated by the variable response to irradiation of tumors which appear similar by light microscopy and other currently utilized features of tumor characterization. The high failure rate from distant metastases within two years of treatment in patients with muscle infiltrating tumors is probably largely a consequence of preexisting metastases unrecognized by current techniques of M categorization. This population of patients might be spared the burden of ag-
Sl!PI'LE~I'IE1'\T
TO APRIL
I
VOLmlE XXIII, NmlBER 4
gressive local treatment if the systemic nature of their disease could be reliably determined before local treatment was started. The occasional therapeutic effectiveness of definitive irradiation and the technical feasibility of "salvage" cystectomy have lent substance to the argument that patients requiring radical treatment for bladder cancer might first be given definitive irradiation with the hope that such treatment would control the cancer and conserve bladder function, but with the realization that if such treatment failed, salvage cystectomy might still be curative. Such an empiric approach emphasizes the need for criteria for predicting radioresponsiveness. Evidence that irradiation may result in rapid disappearance of aneuploid stem cell lines from bladder washings in patients with muscleinfiltrating bladder cancers suggests the possible usefulness of flow cytometry in detecting radioresponsiveness. This finding provides evidence of the therapeutic response heterogeneity of apparently similar bladder tumors. In spite of the low morbidity and mortality of radical cystectomy, it is a major procedure with devastating impacts on the quality if not the quantity of life. Patients "cope" well with the procedure, but this is more a tribute to the human spirit than to surgical skill. Continued efforts to diminish the adverse effects of the procedure on urinary and sexual functions are warranted. Endoscopic applications of laser technology offer potential prospects of local control of T 2 and T 3 tumors and may demonstrate advantages over conventional endoscopic procedures in the control of superficial tumors. Such treatment has been experimentally demonstrated to be capable of producing a controlled coagulation necrosis of the full thickness of bladder wall without subsequent perforation. The use of radiosensitizers or of chemotherapy in conjunction with irradiation for improving radioresponsiveness is another promising area for investigation. Metastatic Tumors (N + and lor M + ) Approximately 5% of patients present with metastatic bladder neoplasm, and approximately half of patients with apparently localized muscleinfiltrating tumors develop evidence of distant metastases within two years. Surgery and irradiation are of limited usefulness in the palliation or cure of metastatic tumors, in contrast to their major roles in local tumor control. The control of metastatic disease continues to depend principally upon either its prevention by earlier diagnosis and effective treatment of local disease or its eradication by systemic therapy. The early appearance of distant metastases
7
in patients treated by cystectomy for bladder cancer provides compelling circumstantial evidence that such individuals harbored occult metastatic disease prior to cystectomy. For patients with metastatic disease in the regional nodes, the prospects of surgical cure or possibly radiation cure, even in the face of limited nodal metastases, are generally in the 10-20 % range. For these and other high risk patients, programs of adjuvant chemotherapy using agents of defined activity are under exploration. An important question is whether any of the current generation of drugs produces high enough complete response rates in patients with advanced measurable disease to render them capable of destroying micrometastases. Perhaps the most that can be expected from the application of adjuvant chemotherapy with the current generation of cytotoxic agents is prolongation of disease free intervals. A further question is whether "adjuvant" treatment of occult metastases offers a survival advantage over treatment of overt recurrence. Randomized clinical trials will help to answer these questions. Phase II studies have defined the activity of a number of single agents against advanced measurable bladder cancer, and Phase III studies designed to compare the effectiveness of various agents, alone or in combination, are in progress. Experimental systems for selecting drugs for the treatment of patients with bladder cancer remain an important con-
8
sideration, and the induction or transplantation of bladder tumors in experimental animals, the clonogenic assayof human tumors in soft agar, and the study of human tumors grown in the nude mouse are test systems currently under investigation. The designation "bladder neoplasm" clearly encompasses a morphologically and biologically heterogeneous group of tumors with various natural histories and with various responses to the same or to different treatments. Although this diversity may ultimately be correlated with definable differences amongst such tumors, morphologic or otherwise, information. is currently insufficient to permit more than gross and tentative distinctions between groups. Apparently similar (morphologically). tumors are treated more or less uniformly, yet may respond differently. Comment Mark Twain characterized the optimist as one who defines the glass as half full in contrast to the pessimist who sees it as half empty, and it would not be amiss to characterize the bladder tumor picture as dark with problems, yet bright with prospects for solutions.
Urologic Service Memorial Sloan-Kettering Cancer Center New York, New York 10021
SUPPLEME1':T TO APRIL
I
VOLUME XXIII, Nm.mER 4