Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Bladder cancer Robert A. Badalament MD & Joseph R. Drago MD To cite this article: Robert A. Badalament MD & Joseph R. Drago MD (1990) Bladder cancer, Postgraduate Medicine, 88:4, 63-70, DOI: 10.1080/00325481.1990.11704753 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704753
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [RMIT University Library]
Date: 15 June 2016, At: 11:06
RIVI
symposium
Second of two articles on hematuria
Bladder cancer What's new in diagnosis and treatment?
propensity to metastasize. For untreated metastatic disease, the 2-year survival rate is less than 5%.4
Postgraduate Medicine 1990.88:63-70.
Initial evaluation
Preview Blood in the urine-sometimes with additional symptoms but sometimes with no pain or other complaint-is the most common presentation of bladder cancer. In this article, initial office evaluation and recently developed diagnostic studies for neoplasia are described. Classification for treatment and approaches to superficial and invasive bladder cancer are also summarized.
Robert A Badalament, MD Joseph R. Drago, MD •:• Bladder cancer is the fourth most prevalent malignant disease among men and the tenth among women in the United States. The American Cancer Society estimated that 47,100 new cases of bladder cancer and 12,600 deaths from bladder cancer would occur in 1989.' Although several substances have been suspected to be causative, only cigarette smoking and occupational exposure to aromatic arnines are wellestablished risk factors. 2 The most common clinical presentation is painless gross hematuria. Early signs may also be microscopic hematuria, irritative voiding symptoms (originally attributed to obstructive uropathy caused by benign
prostatic hypertrophy), and bladder outlet or ureteral obstructive complaints. Bladder cancer may be classified by the TNM staging system (table 1).3 Superficial bladder cancers include turnors in situ (Tis), papillary turnors limited to the mucosa (Ta), and papillary turnors that involve the lamina propria (Tl). Invasive bladder cancer involves the muscularis layer or beyond (T2 to T4). About 75% of newly diagnosed cases of bladder cancer are superficial; the remainder have invaded the bladder muscle or are metastatic. Although superficial bladder turnors have a high recurrence rate, the majority of recurrent turnors are superficial. However, 5% to 30% of superficial turnors progress to invasive disease. Invasive turnors have a high
VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
Transitional cell urothelium lines the urinary tract from the renal papillae to a few centimeters proximal to the urethral meatus. Researchers believe that because it stores urine, the bladder has an increased exposure time to carcinogens, which accounts for the higher incidence of bladder cancer compared with pyeloureteral or urethral cancer. However, because the entire urinary tract is exposed to the same carcinogenic agents and multifocal turnors are common, examination of all urothelial surfaces is mandatory. Although initial diagnosis of bladder cancer is usually made using office cystoscopy and topical anesthesia, definitive evaluation requires general or spinal anesthesia. Bimanual examination should be performed before and after endoscopy. After the endoscope is introduced, urine is collected for cytologic examination and the bladder is irrigated with saline solution fur bladder wash cytologic (figure 1) and/or flow cytometric (figure 2) evaluation. The urethra and bladder are then visualized. Tumor size, number, location, and visual characteristics are recorded photographically (figure 3) or are marked on bladder diagrams. If possible, transurethral resection of all gross turnor and random biopcontinued 63
The presence of aneuploidy on flow cytometry of bladder cells is an early indicator of neoplastic change.
Postgraduate Medicine 1990.88:63-70.
Table 1. TNM system for staging bladder cancer T: primary tumor TO No tumor present Tis Carcinoma in situ Ta Papillary tumor limited to mucosa T1 Extension into but not beyond lamina propria T2 Invasion into superficial muscle layer T3a Invasion into deep muscle layer T3b Invasion into perivesical fat T4a Invasion into adjacent organ (prostate, vagina, uterus) T4b Fixed to pelvic or abdominal wall TX Minimum requirements to assess primary tumor not met N: lymph nodes NO No evidence of lymph node involvement N1 Involvement of single homolateral regional lymph node N2 Involvement of contralateral, bilateral, or multiple regional lymph nodes N3 Involvement of regional lymph nodes, creating fixed mass N4 Involvement of juxtaregional lymph nodes NX Minimum requirements to assess regional and juxtaregionallymph nodes not met M: distant metastasis MO No evidence of distant metastasis M1 Evidence of distant metastasis MX Minimum requirements to assess presence of distant metastasis not met
sies of normal-appearing urothelium should be performed. During initial evaluation, the tumor should be resected deeply, because classification of bladder cancer is based on the depth of tumor penetration into the bladder. Biopsy of grossly normal urothelium permits evaluation of the degree of urothelial field change or the extent of multifocal involvement. Endoscopy of the ureters and renal pelvis is not routinely performed; usually the upper urinary tracts are assessed by intravenous urography.
64
Advances in diagnosis Several recent advances have been made in diagnosis of bladder cancer, including flow cyrometry, flexible endoscopy, and ureteropyeloscopy. Urinary cytology and flow cytometry are ofi:en compared because they provide similar clinical information. Cytology, which is a Pap smear of exfoliated urothelial cells, involves the use of subjective cytologic criteria to estimate DNA content and determine if carcinoma exists. Flow cytometry is an automated, objective method that quantitatively measures
DNA content or ploidy. Cells with a normal DNA content are diploid and cells with an abnormal DNA content are aneuploid. Although diploidy is found in both normal and neoplastic cells, aneuploidy is present only in neoplastic cells. Thus, the presence of aneuploidy is an early indicator of neoplastic change an~ may detect~ b~fore macroscopiC or rrucroscoptc evidence of neoplasm is seen. Formerly a research tool, flow cytometry is starting to be integrated into the clinical management of patients with bladder cancer. It appears to be more sensitive than urinary cytology in the diagnosis ofbladder cancer. 5·6 One flow cytometric evaluation has been shown to be significantly more sensitive than cytologic assessment of three voided urine specimens.5 In a review from Memorial Sloan-Kettering Cancer Center, the sensitiviry of flow cytometry in 528 patients with histologically confirmed bladder cancer was 78%/ In another srudy,8 the specificity of flow cytometry in 100 patients undergoing evaluation for nonneoplastic disease of the bladder was 2%. In general, the frequency of aneuploidy tends to increase with increasing rumor category and grade. Furthermore, researchers from the Karolinska Institute have demonstrated that tumor recurrence and progression in patients with aneuploid tumors are significantly greater than in those with diploid (ie, normal DNA content) tumors. 9•10 Before the 1980s, visual examinacontinued
tJ:
BLADDER CANCER • VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE
Postgraduate Medicine 1990.88:63-70.
Patients with multifocal, high-grade bladder tumors with penetration into the lamina propria are at high risk for recurrence and progression.
cion of the urinary tract was limited to rigid endoscopy of the bladder. The introduction of flexible cystoscopy, which is considerably more comfortable for men than the rigid procedure, facilitates outpatient endoscopic evaluation. Additionally, with the advent of rigid and flexible ureteroscopy, direct visualization of a b the ureters and renal pelvis is possiFigure 1. Results of bladder wash cytologic evaluation. a. Normal cells. b. Neoplastic cells ble. In patients with a solitary kidney (arrows). Cytologic changes attributed to neoplasia include enlarged hyperchromatic nuclei, or poor renal function, bladder canincreased nuclear-cytoplasmic ratio, and coarsely textured chromatin. cer that has spread to the pyeloureteral system may be managed endoscopically with a laser adapted for use through the ureteroscope.
Treatment of superficial bladder cancer After initial evaluation, the turnor is classified as superficial or invasive. If it is superficial, risk factors for turnor recurrence or progression must be assessed to determine proper management. ASSESSMENT-Patients with small, solitary, low-grade diploid tumors that are limited to the mucosa (Ta) are at low risk for recurrence. In these patients, random bladder biopsy specimens of grossly normal urothelium and results of cytologic or flow cytometric examination after transurethral resection are normal. Safe management consists of tranSurethral resection followed by endoscopic, cytologic, and flow cytometric surveillance. Patients with multifocal, highgrade aneuploid turnors with penetration of the basement membrane into the lamina propria (Tl) are at
a
b Figure 2. Diploid DNA histograms of bladder wash specimen in patient with idiopathic gross hematuria (a) and in patient with aneuploid bladder tumor (b). Solid arrows identify diploid cell population and open arrow pinpoints aneuploid cell population.
high risk for turnor recurrence and progression. Typically, random bladder biopsy specimens and cytologic or flow cytometric examination after transurethral resection reveal abnormalities. High-risk patients are candidates for adjuvant intravesical therapy, most commonly with thiotepa, doxorubicin hydrochloride (Adriamycin), mitomycin (Mutamycin), and BCG vaccine. These agents are typically instilled into the bladder through a urethral catheter for 2 hours weekly for 6 weeks.
ADVANCES--Herr and assvciates11 recently compared intravesical agents and concluded that BCG vaccine is the most effective. BCG vaccine is an attenuated strain of Mycobacterium bovis that was first used in 1921 against tuberculosis. Since the original organism has undergone diversification, different strains of BCG vaccine are not necessarily equivalent. Pasteur, 1ice, and Connaught strains of BCG vaccine are those most ofi:en used to treat superficial bladder cancer. The mechanism of action of BCG
continued VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
67
Postgraduate Medicine 1990.88:63-70.
Use of BCG vaccine for superficial bladder cancer has been shown to delay disease recurrence, prolong the period of bladder preservation, and increase the overall survival rate.
Figure 3. Endoscopic appearance of papillary bladder tumor.
vaccine on rumor growth remains undetermined. Either it causes a nonspecific inflammatory response that results in generalized sloughing of the urothelium, or it produces an immunogenic response directed against the malignant cells. Since 1976, when Morales and associates 12 first reponed the use of BCG vaccine in patients with superficial bladder cancer, two prospective randomized trials have been performed. The studies showed that transurethral resection followed by intravesical administration of BCG vaccine significantly reduced the number of recurrent rumors compared with transurethral resection alone. One of these studies was recently updated; patients were followed a mean of 6 years. 13 The report showed that use of BCG vaccine significantly altered the natural history of superficial bladder cancer. The median time to progression (muscle invasion or metastasis) was 12 months in the transurethral resection control group and 60 months 68
in the BCG vaccine group. Use of BCG vaccine also delayed disease recurrence, prolonged the period of bladder preservation, and increased the overall survival rate. Adverse reactions to intravesical BCG vaccine are usually transient. They can include symptoms oflocal bladder irritation (eg, dysuria, frequency, urgency) or of systemic toxicity (low-grade fever and a flulike syndrome that is self-limiting). Occasionally, disseminated infection that involves the lungs or liver develops from the BCG vaccine, which mandates antituberculosis therapy. Several deaths resulting directly from intravesical administration of BCG vaccine have been reponed; trauma occurred during catheterization in a majority of these patients. Neodynium:yttrium-alurninumgarnet lasers have been used to coagulate bladder rumors directly. 14 The advantage of this therapy is that the rumor can be destroyed during office cystoscopy. However, the inability to assess histologically the depth of tumar invasion into the bladder wall has limited its application. Patients with recurrent superficial papillary rumors (Ta), who are at low risk for rumor progression, are good candidates for laser therapy. Phototherapy combines a laser with a photosensitizer (eg, hematoporphyrin derivative) to treat superficial bladder cancer. 15 Phototherapy can be performed 2 to 3 days after administration of the photosensitizer, which has an affinity for neoplastic cells. When light of the appropriate wavelength is introduced, oxygen
singlets that selectively destroy tumar cells are produced. PhototheraPY has not been widely used because marked photosensitivity results, so direct exposure to sunlight must be avoided for up to 4 weeks. Ifshortacting photosensitizers are developed, phototherapy will become a more practical therapeutic option.
Treatment of invasive bladder cancer
Cystectomy is the definitive treatment of invasive bladder cancer. Penoperative nutritional and cardiopulmonary care has decreased mortality and morbidity with this treatment even among high-risk patients. Radiation therapy and systemic chemotherapy have also been successful. STANDARD-The vast majority of patients with muscle-invasive bladder cancer require radical cystectomy and urinary diversion. Those with a single focus of invasive rumor that can be circumscribed by a 2-cm margin may be treated with partial cystectomy. Partial cystectomy allows maintenance of normal voiding and sexual potency. Five-year survival rates for cystectomy range from 44% to 75% in the absence oflymph node involvement. 16 Radiation therapy is generally reserved for poor surgical candidates or patients who refuse surgery. Definitive radiation therapy is not without complications. A study of 529 patients treated with radiation therapy at the University of Texas M. D. Anderson Hospital and Tumor Institute reponed a 5% mortality rate and a 15% rate of major complications. 17
BLADDER CANCER • VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE
Postgraduate Medicine 1990.88:63-70.
With appropriate perioperative care, radical cystectomy and urinary diversion have no higher morbidity and mortality rates in elderly patients than in young patients.
Five-year survival after radiation therapy is 16% to 30%. 16 ADVANCF.S--Hyperalimentation, invasive cardiopulmonary monitoring, and other advances in perioperative care have allowed more complex surgery to be performed on high-risk patients. With appropriate perioperative care, radical cystectomy and urinary diversion have no higher morbidity and mortality rates in elderly patients than in young patients. 18 These advances have enhanced survival rates because the number of patients who can undergo definitive surgical treatment is higher now than in the past. The majority of patients treated with radical cystectomy have an ileal conduit urinary diversion into an external appliance. Although many continent urinary diversions have recently been described, there are basically two types. 19 All continent urinary diversions involve the creation of an intra-abdominal reservoir using bowel. With one type, the patient must catheterize the reservoir via a small stoma that is flush with the skin. The catheter must traverse a continence mechanism, which either has been created by the surgeon or uses the ileocecal valve. The patient does not require a drainage bag and between catheterizations wears a small dressing over the stoma. With the other type, used only in men, the reservoir is attached to an intact urethra and the patient's own external urinary sphincter is the continence mechanism. There is no stoma, and many men are able to
Robert A. Badalament, MD Joseph R. Drago, MD Dr Badalament (right) is assistant professor and Dr Drago (left) is the Louis Levy Professor of Cancer and chairman, division of urology, Ohio State University College of Medicine, Columbus.
void spontaneously by increasing intra-abdominal pressure. Continent urinary diversion greatly enhances the quality of the patient's life after cystectomy. However, compared with ileal conduit surgery, it is a longer procedure and has been associated with significantly increased rates of postoperative complications, including the need for surgical revision. Advanced bladder cancer was once believed to be relatively insensitive to chemotherapy. However, clinical trials have identified cisplatin (Platinol) and methotrexate (Folex, Mexate) as the two most effective single agents for this cancer. Additionally, a synergistic effect was seen
VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
when cisplatin and doxorubicin were used in combination and when administration of methotrexate preceded that of vinblastine sulfate (Velban, Velsar). These fuur chemotherapeutic agents were combined at the Memorial Sloan-Kettering Cancer Center to form the M-VAC regimen. The M-VAC chemotherapeutic regimen has produced frequent and lasting remissions in patients with invasive and/or metastatic bladder cancer. Recently, results of treatment of the first 83 assessable patients with lymph node or distant metastatic transitional cell carcinoma of the bladder were reported. 20 The overall response rate was 69%. Complete and partial response rates were 37% continued 69
Postgraduate Medicine 1990.88:63-70.
and 31 o/o, respectively. The median survival of patients with complete response has not been reached but will exceed 26 months. The 1-, 2-, and 3-year survival rates were 93o/o, 71 o/o, and 55o/o, respectively. Slightly less effective results have been reponed by the Northern California Oncology Group with the cisplatin-methotrexate-vinblastine regimen and by the University of Texas M. D. Anderson Hospital and Tumor Institute with the cisplatincyclophospharnide {Neosar)-doxorubicin regimen. 21 '22 Preoperative chemotherapy may shrink an invasive bladder tumor enough to permit radical cystectomy of a formerly unresectable tumor or partial instead of radical cystectomy. Although these preliminary re-
ports are encouraging, the patients treated represent a select group, and follow-up has been relatively short. Long-term studies are needed to better define the efficacy of systemic chemotherapy in patients with advanced bladder cancer. Summary Advances in diagnosis and treatment hal'e im_prol'a( survival rates, bladder preservation, and quality of lire in patients with bladder cancer. How cytometry and flexible endoscopy hal'e enhanced
Systemic chemotherapy is effective in patients with invame and metastatic bladder cancer. Although these advances are enoouraging, oontinued inwstigation is requiral to further impi'O\'e bladder preservation and survival rates, and clinical appliati.on of laser therapy and-phototherapy needs to be fully developed. Fall
-®
Earn credit on this article. See CME Quiz.
This work was funded in part by the Ohio State University Urologic Development and Research Fund, Columbus.
early diagnosis, and inmnaical use of BCG wccine has decreased the rate of recurrence and progression of superficial bladder cancer.
Address for correspondence: Joseph R Drago, MD, 456W lOthAve, Columbus, OH 43210.
the bladder: an estimate of the fulse positive rate. J Urol!982;127(5):946-8 9. Gusta&on H, Tribukait 8, Esposti PL DNA pattern, histological grade and muftiplicity related to recurrence rate in superficial bladder tumours. ScandJ Urol Nephrol!982;16(2):135-9 10. Gusta&on H, Tribukait 8, &posti PL DNA profile and tumour progression in patienlli with superficial bladder tumours. Urol Res 1982;10(1):13-8 11. Herr UW, Laudone VP, Whitmore WF Jr. An overview of intravesical therapy fur superficial bladder tumors. J Urol!987;138(6):1363-8 12. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treaunent of superficial bladder tumors. J Urol1976;116(2): 180-3 13. Herr UW, Laudone VP, Badalament RA, et al. Bacillus Calmerte-Guerin therapy alters the progression of superficial bladder cancer. J Clin Oncol 1988;6(9):1450-5 14. Smith JA Jr. Endoscopic applications of laser energy. Urol Clin North Am 1986; 13(3):405-19 15. Prout GRJr, I..in CW, Demon RJr, et al. Photodynamic therapy with hematoporphyrin derivative in the treaunent of superficial transitional-
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Bladder cancer Robert A. Badalament MD & Joseph R. Drago MD To cite this article: Robert A. Badalament MD & Joseph R. Drago MD (1990) Bladder cancer, Postgraduate Medicine, 88:4, 63-70, DOI: 10.1080/00325481.1990.11704753 To link to this article: http://dx.doi.org/10.1080/00325481.1990.11704753
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [RMIT University Library]
Date: 15 June 2016, At: 11:06
RIVI
symposium
Second of two articles on hematuria
Bladder cancer What's new in diagnosis and treatment?
propensity to metastasize. For untreated metastatic disease, the 2-year survival rate is less than 5%.4
Postgraduate Medicine 1990.88:63-70.
Initial evaluation
Preview Blood in the urine-sometimes with additional symptoms but sometimes with no pain or other complaint-is the most common presentation of bladder cancer. In this article, initial office evaluation and recently developed diagnostic studies for neoplasia are described. Classification for treatment and approaches to superficial and invasive bladder cancer are also summarized.
Robert A Badalament, MD Joseph R. Drago, MD •:• Bladder cancer is the fourth most prevalent malignant disease among men and the tenth among women in the United States. The American Cancer Society estimated that 47,100 new cases of bladder cancer and 12,600 deaths from bladder cancer would occur in 1989.' Although several substances have been suspected to be causative, only cigarette smoking and occupational exposure to aromatic arnines are wellestablished risk factors. 2 The most common clinical presentation is painless gross hematuria. Early signs may also be microscopic hematuria, irritative voiding symptoms (originally attributed to obstructive uropathy caused by benign
prostatic hypertrophy), and bladder outlet or ureteral obstructive complaints. Bladder cancer may be classified by the TNM staging system (table 1).3 Superficial bladder cancers include turnors in situ (Tis), papillary turnors limited to the mucosa (Ta), and papillary turnors that involve the lamina propria (Tl). Invasive bladder cancer involves the muscularis layer or beyond (T2 to T4). About 75% of newly diagnosed cases of bladder cancer are superficial; the remainder have invaded the bladder muscle or are metastatic. Although superficial bladder turnors have a high recurrence rate, the majority of recurrent turnors are superficial. However, 5% to 30% of superficial turnors progress to invasive disease. Invasive turnors have a high
VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
Transitional cell urothelium lines the urinary tract from the renal papillae to a few centimeters proximal to the urethral meatus. Researchers believe that because it stores urine, the bladder has an increased exposure time to carcinogens, which accounts for the higher incidence of bladder cancer compared with pyeloureteral or urethral cancer. However, because the entire urinary tract is exposed to the same carcinogenic agents and multifocal turnors are common, examination of all urothelial surfaces is mandatory. Although initial diagnosis of bladder cancer is usually made using office cystoscopy and topical anesthesia, definitive evaluation requires general or spinal anesthesia. Bimanual examination should be performed before and after endoscopy. After the endoscope is introduced, urine is collected for cytologic examination and the bladder is irrigated with saline solution fur bladder wash cytologic (figure 1) and/or flow cytometric (figure 2) evaluation. The urethra and bladder are then visualized. Tumor size, number, location, and visual characteristics are recorded photographically (figure 3) or are marked on bladder diagrams. If possible, transurethral resection of all gross turnor and random biopcontinued 63
The presence of aneuploidy on flow cytometry of bladder cells is an early indicator of neoplastic change.
Postgraduate Medicine 1990.88:63-70.
Table 1. TNM system for staging bladder cancer T: primary tumor TO No tumor present Tis Carcinoma in situ Ta Papillary tumor limited to mucosa T1 Extension into but not beyond lamina propria T2 Invasion into superficial muscle layer T3a Invasion into deep muscle layer T3b Invasion into perivesical fat T4a Invasion into adjacent organ (prostate, vagina, uterus) T4b Fixed to pelvic or abdominal wall TX Minimum requirements to assess primary tumor not met N: lymph nodes NO No evidence of lymph node involvement N1 Involvement of single homolateral regional lymph node N2 Involvement of contralateral, bilateral, or multiple regional lymph nodes N3 Involvement of regional lymph nodes, creating fixed mass N4 Involvement of juxtaregional lymph nodes NX Minimum requirements to assess regional and juxtaregionallymph nodes not met M: distant metastasis MO No evidence of distant metastasis M1 Evidence of distant metastasis MX Minimum requirements to assess presence of distant metastasis not met
sies of normal-appearing urothelium should be performed. During initial evaluation, the tumor should be resected deeply, because classification of bladder cancer is based on the depth of tumor penetration into the bladder. Biopsy of grossly normal urothelium permits evaluation of the degree of urothelial field change or the extent of multifocal involvement. Endoscopy of the ureters and renal pelvis is not routinely performed; usually the upper urinary tracts are assessed by intravenous urography.
64
Advances in diagnosis Several recent advances have been made in diagnosis of bladder cancer, including flow cyrometry, flexible endoscopy, and ureteropyeloscopy. Urinary cytology and flow cytometry are ofi:en compared because they provide similar clinical information. Cytology, which is a Pap smear of exfoliated urothelial cells, involves the use of subjective cytologic criteria to estimate DNA content and determine if carcinoma exists. Flow cytometry is an automated, objective method that quantitatively measures
DNA content or ploidy. Cells with a normal DNA content are diploid and cells with an abnormal DNA content are aneuploid. Although diploidy is found in both normal and neoplastic cells, aneuploidy is present only in neoplastic cells. Thus, the presence of aneuploidy is an early indicator of neoplastic change an~ may detect~ b~fore macroscopiC or rrucroscoptc evidence of neoplasm is seen. Formerly a research tool, flow cytometry is starting to be integrated into the clinical management of patients with bladder cancer. It appears to be more sensitive than urinary cytology in the diagnosis ofbladder cancer. 5·6 One flow cytometric evaluation has been shown to be significantly more sensitive than cytologic assessment of three voided urine specimens.5 In a review from Memorial Sloan-Kettering Cancer Center, the sensitiviry of flow cytometry in 528 patients with histologically confirmed bladder cancer was 78%/ In another srudy,8 the specificity of flow cytometry in 100 patients undergoing evaluation for nonneoplastic disease of the bladder was 2%. In general, the frequency of aneuploidy tends to increase with increasing rumor category and grade. Furthermore, researchers from the Karolinska Institute have demonstrated that tumor recurrence and progression in patients with aneuploid tumors are significantly greater than in those with diploid (ie, normal DNA content) tumors. 9•10 Before the 1980s, visual examinacontinued
tJ:
BLADDER CANCER • VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE
Postgraduate Medicine 1990.88:63-70.
Patients with multifocal, high-grade bladder tumors with penetration into the lamina propria are at high risk for recurrence and progression.
cion of the urinary tract was limited to rigid endoscopy of the bladder. The introduction of flexible cystoscopy, which is considerably more comfortable for men than the rigid procedure, facilitates outpatient endoscopic evaluation. Additionally, with the advent of rigid and flexible ureteroscopy, direct visualization of a b the ureters and renal pelvis is possiFigure 1. Results of bladder wash cytologic evaluation. a. Normal cells. b. Neoplastic cells ble. In patients with a solitary kidney (arrows). Cytologic changes attributed to neoplasia include enlarged hyperchromatic nuclei, or poor renal function, bladder canincreased nuclear-cytoplasmic ratio, and coarsely textured chromatin. cer that has spread to the pyeloureteral system may be managed endoscopically with a laser adapted for use through the ureteroscope.
Treatment of superficial bladder cancer After initial evaluation, the turnor is classified as superficial or invasive. If it is superficial, risk factors for turnor recurrence or progression must be assessed to determine proper management. ASSESSMENT-Patients with small, solitary, low-grade diploid tumors that are limited to the mucosa (Ta) are at low risk for recurrence. In these patients, random bladder biopsy specimens of grossly normal urothelium and results of cytologic or flow cytometric examination after transurethral resection are normal. Safe management consists of tranSurethral resection followed by endoscopic, cytologic, and flow cytometric surveillance. Patients with multifocal, highgrade aneuploid turnors with penetration of the basement membrane into the lamina propria (Tl) are at
a
b Figure 2. Diploid DNA histograms of bladder wash specimen in patient with idiopathic gross hematuria (a) and in patient with aneuploid bladder tumor (b). Solid arrows identify diploid cell population and open arrow pinpoints aneuploid cell population.
high risk for turnor recurrence and progression. Typically, random bladder biopsy specimens and cytologic or flow cytometric examination after transurethral resection reveal abnormalities. High-risk patients are candidates for adjuvant intravesical therapy, most commonly with thiotepa, doxorubicin hydrochloride (Adriamycin), mitomycin (Mutamycin), and BCG vaccine. These agents are typically instilled into the bladder through a urethral catheter for 2 hours weekly for 6 weeks.
ADVANCES--Herr and assvciates11 recently compared intravesical agents and concluded that BCG vaccine is the most effective. BCG vaccine is an attenuated strain of Mycobacterium bovis that was first used in 1921 against tuberculosis. Since the original organism has undergone diversification, different strains of BCG vaccine are not necessarily equivalent. Pasteur, 1ice, and Connaught strains of BCG vaccine are those most ofi:en used to treat superficial bladder cancer. The mechanism of action of BCG
continued VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
67
Postgraduate Medicine 1990.88:63-70.
Use of BCG vaccine for superficial bladder cancer has been shown to delay disease recurrence, prolong the period of bladder preservation, and increase the overall survival rate.
Figure 3. Endoscopic appearance of papillary bladder tumor.
vaccine on rumor growth remains undetermined. Either it causes a nonspecific inflammatory response that results in generalized sloughing of the urothelium, or it produces an immunogenic response directed against the malignant cells. Since 1976, when Morales and associates 12 first reponed the use of BCG vaccine in patients with superficial bladder cancer, two prospective randomized trials have been performed. The studies showed that transurethral resection followed by intravesical administration of BCG vaccine significantly reduced the number of recurrent rumors compared with transurethral resection alone. One of these studies was recently updated; patients were followed a mean of 6 years. 13 The report showed that use of BCG vaccine significantly altered the natural history of superficial bladder cancer. The median time to progression (muscle invasion or metastasis) was 12 months in the transurethral resection control group and 60 months 68
in the BCG vaccine group. Use of BCG vaccine also delayed disease recurrence, prolonged the period of bladder preservation, and increased the overall survival rate. Adverse reactions to intravesical BCG vaccine are usually transient. They can include symptoms oflocal bladder irritation (eg, dysuria, frequency, urgency) or of systemic toxicity (low-grade fever and a flulike syndrome that is self-limiting). Occasionally, disseminated infection that involves the lungs or liver develops from the BCG vaccine, which mandates antituberculosis therapy. Several deaths resulting directly from intravesical administration of BCG vaccine have been reponed; trauma occurred during catheterization in a majority of these patients. Neodynium:yttrium-alurninumgarnet lasers have been used to coagulate bladder rumors directly. 14 The advantage of this therapy is that the rumor can be destroyed during office cystoscopy. However, the inability to assess histologically the depth of tumar invasion into the bladder wall has limited its application. Patients with recurrent superficial papillary rumors (Ta), who are at low risk for rumor progression, are good candidates for laser therapy. Phototherapy combines a laser with a photosensitizer (eg, hematoporphyrin derivative) to treat superficial bladder cancer. 15 Phototherapy can be performed 2 to 3 days after administration of the photosensitizer, which has an affinity for neoplastic cells. When light of the appropriate wavelength is introduced, oxygen
singlets that selectively destroy tumar cells are produced. PhototheraPY has not been widely used because marked photosensitivity results, so direct exposure to sunlight must be avoided for up to 4 weeks. Ifshortacting photosensitizers are developed, phototherapy will become a more practical therapeutic option.
Treatment of invasive bladder cancer
Cystectomy is the definitive treatment of invasive bladder cancer. Penoperative nutritional and cardiopulmonary care has decreased mortality and morbidity with this treatment even among high-risk patients. Radiation therapy and systemic chemotherapy have also been successful. STANDARD-The vast majority of patients with muscle-invasive bladder cancer require radical cystectomy and urinary diversion. Those with a single focus of invasive rumor that can be circumscribed by a 2-cm margin may be treated with partial cystectomy. Partial cystectomy allows maintenance of normal voiding and sexual potency. Five-year survival rates for cystectomy range from 44% to 75% in the absence oflymph node involvement. 16 Radiation therapy is generally reserved for poor surgical candidates or patients who refuse surgery. Definitive radiation therapy is not without complications. A study of 529 patients treated with radiation therapy at the University of Texas M. D. Anderson Hospital and Tumor Institute reponed a 5% mortality rate and a 15% rate of major complications. 17
BLADDER CANCER • VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE
Postgraduate Medicine 1990.88:63-70.
With appropriate perioperative care, radical cystectomy and urinary diversion have no higher morbidity and mortality rates in elderly patients than in young patients.
Five-year survival after radiation therapy is 16% to 30%. 16 ADVANCF.S--Hyperalimentation, invasive cardiopulmonary monitoring, and other advances in perioperative care have allowed more complex surgery to be performed on high-risk patients. With appropriate perioperative care, radical cystectomy and urinary diversion have no higher morbidity and mortality rates in elderly patients than in young patients. 18 These advances have enhanced survival rates because the number of patients who can undergo definitive surgical treatment is higher now than in the past. The majority of patients treated with radical cystectomy have an ileal conduit urinary diversion into an external appliance. Although many continent urinary diversions have recently been described, there are basically two types. 19 All continent urinary diversions involve the creation of an intra-abdominal reservoir using bowel. With one type, the patient must catheterize the reservoir via a small stoma that is flush with the skin. The catheter must traverse a continence mechanism, which either has been created by the surgeon or uses the ileocecal valve. The patient does not require a drainage bag and between catheterizations wears a small dressing over the stoma. With the other type, used only in men, the reservoir is attached to an intact urethra and the patient's own external urinary sphincter is the continence mechanism. There is no stoma, and many men are able to
Robert A. Badalament, MD Joseph R. Drago, MD Dr Badalament (right) is assistant professor and Dr Drago (left) is the Louis Levy Professor of Cancer and chairman, division of urology, Ohio State University College of Medicine, Columbus.
void spontaneously by increasing intra-abdominal pressure. Continent urinary diversion greatly enhances the quality of the patient's life after cystectomy. However, compared with ileal conduit surgery, it is a longer procedure and has been associated with significantly increased rates of postoperative complications, including the need for surgical revision. Advanced bladder cancer was once believed to be relatively insensitive to chemotherapy. However, clinical trials have identified cisplatin (Platinol) and methotrexate (Folex, Mexate) as the two most effective single agents for this cancer. Additionally, a synergistic effect was seen
VOL 88/NO 4/SEPTEMBER 15, 1990/POSTGRADUATE MEDICINE • BLADDER CANCER
when cisplatin and doxorubicin were used in combination and when administration of methotrexate preceded that of vinblastine sulfate (Velban, Velsar). These fuur chemotherapeutic agents were combined at the Memorial Sloan-Kettering Cancer Center to form the M-VAC regimen. The M-VAC chemotherapeutic regimen has produced frequent and lasting remissions in patients with invasive and/or metastatic bladder cancer. Recently, results of treatment of the first 83 assessable patients with lymph node or distant metastatic transitional cell carcinoma of the bladder were reported. 20 The overall response rate was 69%. Complete and partial response rates were 37% continued 69
Postgraduate Medicine 1990.88:63-70.
and 31 o/o, respectively. The median survival of patients with complete response has not been reached but will exceed 26 months. The 1-, 2-, and 3-year survival rates were 93o/o, 71 o/o, and 55o/o, respectively. Slightly less effective results have been reponed by the Northern California Oncology Group with the cisplatin-methotrexate-vinblastine regimen and by the University of Texas M. D. Anderson Hospital and Tumor Institute with the cisplatincyclophospharnide {Neosar)-doxorubicin regimen. 21 '22 Preoperative chemotherapy may shrink an invasive bladder tumor enough to permit radical cystectomy of a formerly unresectable tumor or partial instead of radical cystectomy. Although these preliminary re-
ports are encouraging, the patients treated represent a select group, and follow-up has been relatively short. Long-term studies are needed to better define the efficacy of systemic chemotherapy in patients with advanced bladder cancer. Summary Advances in diagnosis and treatment hal'e im_prol'a( survival rates, bladder preservation, and quality of lire in patients with bladder cancer. How cytometry and flexible endoscopy hal'e enhanced
Systemic chemotherapy is effective in patients with invame and metastatic bladder cancer. Although these advances are enoouraging, oontinued inwstigation is requiral to further impi'O\'e bladder preservation and survival rates, and clinical appliati.on of laser therapy and-phototherapy needs to be fully developed. Fall
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Earn credit on this article. See CME Quiz.
This work was funded in part by the Ohio State University Urologic Development and Research Fund, Columbus.
early diagnosis, and inmnaical use of BCG wccine has decreased the rate of recurrence and progression of superficial bladder cancer.
Address for correspondence: Joseph R Drago, MD, 456W lOthAve, Columbus, OH 43210.
the bladder: an estimate of the fulse positive rate. J Urol!982;127(5):946-8 9. Gusta&on H, Tribukait 8, Esposti PL DNA pattern, histological grade and muftiplicity related to recurrence rate in superficial bladder tumours. ScandJ Urol Nephrol!982;16(2):135-9 10. Gusta&on H, Tribukait 8, &posti PL DNA profile and tumour progression in patienlli with superficial bladder tumours. Urol Res 1982;10(1):13-8 11. Herr UW, Laudone VP, Whitmore WF Jr. An overview of intravesical therapy fur superficial bladder tumors. J Urol!987;138(6):1363-8 12. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette-Guerin in the treaunent of superficial bladder tumors. J Urol1976;116(2): 180-3 13. Herr UW, Laudone VP, Badalament RA, et al. Bacillus Calmerte-Guerin therapy alters the progression of superficial bladder cancer. J Clin Oncol 1988;6(9):1450-5 14. Smith JA Jr. Endoscopic applications of laser energy. Urol Clin North Am 1986; 13(3):405-19 15. Prout GRJr, I..in CW, Demon RJr, et al. Photodynamic therapy with hematoporphyrin derivative in the treaunent of superficial transitional-
