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Brain Metastases from Transitional Cell Carcinoma of the Bladder
0022-534 7/88/1404-0820$02.00/0
Vol. 140, October Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
BRAIN METASTASES FROM TRANSITIONAL CELL CARCINOMA OF THE BLADDER JOHN N. KABALIN, FUAD S. FREIHA AND FRANK M. TORTI From the Divisions of Urology and Oncology, and the Stanford GU Oncology Clinic, Stanford University Medical Center and Palo Alto Veterans Administration Medical Center, Stanford, California
ABSTRACT
We present our experience with 4 patients with transitional cell carcinoma of the bladder and brain metastases. In all 4 cases a solitary intracranial metastasis occurred. In 3 patients this represented the first site of recurrent disease following systemic chemotherapy. Aggressive therapy of the brain metastases was instituted in 3 patients, including external beam radiation and in 2 cases surgical resection. Although all patients died only 3 died as a result of metastatic transitional cell carcinoma, including 2 who died as a direct result of intracranial disease. A review of the literature suggests an increasing incidence of brain metastases from transitional cell carcinoma of the bladder with the advent of more aggressive therapy for bladder cancer, which includes radical surgery for high stage disease and combination chemotherapy. Aggressive intervention for solitary brain metastases from transitional cell carcinoma can relieve neurological dysfunction and may prolong survival. (J. Ural., 140: 820-824, 1988) Common sites for metastases from transitional cell carcinoma of the bladder include lymph nodes, lung, bone, liver and adrenal gland. The recent literature suggests an increasing incidence of central nervous system involvement by transitional cell carcinoma metastases 1- 12 associated with the expanding use of systemic combination chemotherapy in the treatment of patients with advanced disease. We describe 4 patients seen by us since 1983 with transitional cell carcinoma metastases to the brain. All lesions were solitary, and they involved the cerebrum in 2 cases and the cerebellum in 2 (see table). In 3 patients metastasis to the brain developed after treatment with cisplatin, methotrexate and vinblastine combination chemotherapy. 12 CASE REPORTS
Case 1. A. M., a 62-year-old woman, presented in March 1982 with complaints of progressive urinary frequency and dysuria during the preceding several months and the new onset of gross hematuria. A large, fixed anterior mass was palpated on pelvic examination. Excretory urography showed moderate bilateral hydronephrosis with ureterectasis to the level of the ureterovesical junctions. Serum creatinine was 1.9 mg./dl. (normal 0.5 to 1.4). Malignant cells were found in a urine cytology specimen. Cystoscopy revealed no distinct tumor but diffuse edema and erythema of the bladder were noted. Neither ureteral orifice could be seen. Bladder biopsies showed grade IV transitional cell carcinoma. A computerized tomography (CT) scan of the abdomen and pelvis showed a large mass involving the bladder dome and invading the uterus posteriorly and the abdominal wall anteriorly. No evidence of intra-abdominal lymphadenopathy or metastasis was seen and a chest x-ray also showed no evidence of metastatic disease. Bipedal lymphangiography was normal. Three cycles of cisplatin, methotrexate and vinblastine chemotherapy were administered followed by 4,500 rad external beam radiation to the pelvis. By July pelvic examination revealed no palpable mass. Repeat CT scan showed resolution of the hydronephrosis bilaterally and a marked reduction in the size of the bladder mass_ Cystoscopy and bladder biopsy confirmed persistent grade III transitional cell carcinoma. A fourth Accepted for publication January 28, 1988.
cycle of cisplatin, methotrexate and vinblastine was administered and another CT scan was obtained in September, which showed only anterior bladder wall thickening. An abdominal CT scan and a chest x-ray continued to show no evidence of lymphadenopathy or metastasis. Serum creatinine was 1. 7. Surgical exploration on October 7 confirmed these findings and anterior pelvic exenteration with ileal loop urinary diversion was performed. Pathological examination showed multifocal grade III transitional cell carcinoma infiltrating the submucosa but no evidence of muscle invasion. The perivesical tissues and lymph nodes were not involved by tumor. Initially the patient did well after cystectomy and she was discharged from the hospital 14 days postoperatively. In February 1983 she was seen for complaints of left hip pain but otherwise she was well. Plain film x-rays and a nuclear bone scan showed no abnormalities. On March 6 the patient was hospitalized because of nausea, vomiting, dehydration and increasing confusion several days in duration. She experienced some difficulty with ambulation but no focal neurological abnormality was identified. Despite intravenous rehydration she became comatose within 24 hours after hospitalization and she died shortly thereafter. Postmortem examination showed a single 3 X 2 X 2 cm. transitional cell carcinoma metastasis in the right cerebellar hemisphere and evidence of brainstem herniation. No other sites of residual disease or metastasis were present in the pelvis, abdomen or chest. Case 2. A. S., a 59-year-old man, presented with total gross painless hematuria in October 1982. Cystoscopy revealed extensive bladder tumor and transurethral resection showed grade IV transitional cell carcinoma with muscle invasion. An IVP demonstrated normal upper tracts bilaterally. Although a chest x-ray, bone scan and CT scan of the abdomen showed no evidence of metastases, exploration in November revealed gross bilateral pelvic lymphadenopathy and biopsies were positive for metastatic transitional cell carcinoma. Cystoprostatectomy with ileal loop diversion was performed with no attempt at lymphadenectomy. Pathological examination of this resection showed grade III to IV transitional cell carcinoma with muscle invasion and carcinoma in situ extending into the prostatic urethra. A single small focus of prostatic adenocarcinoma also was present.
820
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BRAIN Iv1E'TASTASES FROM TRANSI'HONAL CELL CARCINOi\iIA OF BLADDER
OLI.
Sumniary of 4 patients with brain, rnetastases frorn transitional cell carcinorn,a of the b!,{1dde? Case 1
Pt. age
62
Surgical pathology
Multifocal, grade III transitional cell Ca A2 4 cycles cisplatin, methotrexate and vinblastine 4,500
Surgical stage Chemotherapy
Local radiotherapy (rad) Interval between surgical resection and presentation with brain metastasis (mos.) Site of brain metastasis Treatment of brain metastasis Interval between presentation with brain metastasis and death Cause of death
Case 3
Case 2
Case 4
59 66 74 Grade III-IV transitional cell Ca with muscle invasion and presence of focal Ca in situ
Dl
Dl
6 cycles cisplatin, methotrexate and vinblastine None 20
6 cycles cisplatin, methotrexate and vinblastine 2,000 7
Frontal lobe 5,500 rad
Days
Lt. frontoparietal lobe Resection and 3,000 rad 4 mos.
4 mos.
Cerebellum Resection and 4,000 rad 4 mos.
Brain metastasis
Abdominal metastases
Sepsis
Brain metastasis
5
Cerebellum None
Beginning in January 1983 the patient received a total of 6 cycles of cisplatin, methotrexate and vinblastine chemotherapy. A followup CT scan of the abdomen and pelvis in November showed a persistent 5 X 3 cm. lymph node mass in the area of the right common iliac chain. In December laparotomy was performed and the right iliac mass was resected but no other evidence of intra-abdominal disease was found. Pathological examination of the mass showed fibrosis and no evidence of tumor. The patient was well until July 1984 when he presented with complaints of left temporal headaches, garbled speech and mild right hemiparesis. A CT scan of the brain showed a 3 X 3 cm. left frontoparietal mass (fig. 1). A chest x-ray and bone scan showed no evidence of other metastatic disease. Craniotomy and resection of the mass confirmed metastatic transitional cell carcinoma. The patient received 3,000 rad whole brain external beam radiation postoperatively and all neurological symptoms resolved. In October he returned with small bowel obstruction and exploratmy laparotomy revealed a single large mass involving the ileum and omentum. The mass, omentum and a segment of ileum were resected and primary enteroenterostomy was performed. Pathological examination revealed metastatic transitional cell carcinoma. The patient was discharged from the hospital in good condition but within a month a recurrent abdominal mass was easily palpable and he had become severely cachectic. He died within 48 hours of rehospitalization for terminal care. Case 3. M. R., a 66-year-old man, first presented with total gross hematuria associated with vague pelvic discomfort in June 1985. Cystoscopy showed a large tumor at the bladder dome and transurethral resection was performed. Pathological report was grade III to IV transitional cell carcinoma with muscle invasion and carcinoma in situ. The patient received 2,000 rad external beam radiation followed by partial cystectomy in August. A single right external iliac node contained metastatic tumor, and tumor also was present at the surgical margin of the bladder specimen. Between September and December he received 4 cycles of cisplatin, methotrexate and vinblastine combination chemotherapy. A chest x-ray, bone scan and CT scan of the abdomen and pelvis failed to demonstrate definite evidence of metastases and in February 1986 radical cystectomy with a Camey ileal bladder substitution was performed. The resected specimen showed no evidence of residual transitional cell carcinoma in the bladder or lymph nodes, including the periaortic nodes. There were several small foci of prostatic adenocarcinoma (Gleason 3+3) confined to the prostate gland. Two further
C None
None 1
FIG. L Case 2. Contrast CT scan of brain shows left frontoparietal mass with ring enhancement and central areas of cystic necrosis.
cycles of cisplatin, methotrexate and vinblastine therapy were administered postoperatively. In June the patient first complained of right rib pain. A bone scan in September showed increased uptake in the right sixth rib. Biopsy revealed atypical cells but no definite evidence of malignancy. Prostatic acid phosphatase level was normaL The patient was noticed by the family to be progressively disoriented and experiencing difficulty especially with short-term memory loss. He had regained continence after the Camey procedure but he now was incontinent of urine and he complained of frontal headaches. A CT scan of the head showed a 4 x 4 cm. midline frontal brain mass (fig. 2, A). Stereotactic needle biopsy was positive for metastatic transitional cell carcinoma of high grade. The patient was treated with 5,500 rad whole brain external beam radiation, as well as 2,000 rad directed to the right sixth rib. Mental status returned to normal and a CT scan in November showed reduction in the size of the brain lesion (fig. 2, B). A chest x-ray remained clear. In December the patient presented with a new left lower quadrant fistula draining through the site of the previous Penrose drain placement for cystectomy. The drainage ap-
822
KABALIN, FREIHA AND TORTI
FIG. 2. Case 3. A, contrast CT scan of brain shows enhancing frontal mass almost in midline. There is extensive area of cerebral edema surrounding tumor. B, repeat CT scan after 5,500 rad external beam radiation reveals marked diminution in size of lesion.
peared to consist of liquid stool and urine. A fistulogram confirmed communication with the Camey ileal bladder but a loopogram, barium enema and small bowel series failed to demonstrate a communication with the gastrointestinal tract. He was managed conservatively with Foley catheter drainage of the Camey loop, and the fistula closed spontaneously. The patient returned in January 1987 with severe diarrhea several days in duration, the fistula was reopened and draining, and he appeared septic. Serum potassium was 1.9 mEq./1. (normal 3.5 to 5.3) with a serum bicarbonate of 15 mEq./1. (normal 24 to 31) and a creatinine of 1.2. Prostate specific antigen level was 0.0 ng./ml. (normal 0.0 to 2.5). He progressed rapidly into septic shock. Cultures of the urine, fistula drainage and blood yielded large numbers of Escherichia coli. Despite vigorous attempts at resuscitation the patient died within 72 hours of hospitalization of overwhelming sepsis. Postmortem examination showed no evidence of persistent or recurrent tumor in the abdomen or pelvis. Case 4. B. M., a 74-year-old man, first presented with total gross painless hematuria in 1979. He had undergone transurethral resection of a bladder tumor in Iran and the pathological report was unavailable. The patient was followed with no evidence of recurrence until October 1986 when he presented with hematuria and irritative bladder symptoms. Multiple papillary tumors were found at cystoscopy and transurethral resection revealed areas of grade IV transitional cell carcinoma with focal muscle invasion. He was referred to our hospital, and a chest x-ray and CT scan of the abdomen and pelvis showed no evidence of metastases. In January 1987 radical cystectomy with a hemi-Kock ileal bladder substitution was performed. Pathological examination revealed multiple grade III to IV papillary transitional cell carcinoma lesions with muscle invasion and extension into perivesical fat. Multifocal carcinoma in situ also was present. All lymph nodes and surgical margins were clear of tumor. The patient was rehospitalized in February for complaints of nausea and dizziness with no focal neurological findings. He was initially treated for the diagnosis of viral labyrinthitis. Shortly after hospitalization he suffered a pulmonary embolus requiring systemic anticoagulation. The nausea and vertigo did not improve and he began to experience severe headaches. A CT scan (fig. 3, A) and magnetic resonance imaging (fig. 3, B) of the brain revealed a 3 cm. left cerebellar mass with obstruction of the fourth ventricle. Anticoagulant therapy was discontinued and resection of the left cerebellar hemisphere was performed. Pathological examination revealed poorly differen-
tiated metastatic transitional cell carcinoma. The patient did well after this procedure and he was discharged from the hospital after adequate oral anticoagulation with sodium warfarin. Postoperative brain radiation was recommended but refused by the patient. In April he was rehospitalized with oliguria, a creatinine of 4.3 and a serum potassium of 6.4. Ultrasound showed bilateral hydronephrosis and bilateral percutaneous nephrostomy tubes were placed. Serum creatinine and electrolytes normalized. Antegrade nephrostograms demonstrated bilateral distal ureteral obstruction at the anastomoses with the hemi-Kock pouch. A chest x-ray remained clear. A repeat CT scan of the brain showed recurrence of the cerebellar tumor. With his consent the patient received 3,000 rad external beam radiation to the whole brain and 4,000 rad to the posterior fossa through June. Within a week of completing the radiation therapy he returned with increasing lethargy, weakness and dehydration secondary to diminishing oral intake. The deterioration was believed to be owing to progression of the intracranial metastatic tumor. He and his family refused further diagnostic or therapeutic intervention other than intravenous hydration. He became comatose and died 9 days after hospitalization. Postmortem examination was refused. DISCUSSION
Metastasis to the brain from transitional cell carcinoma of the bladder is unusual. It has rarely been encountered as part of the clinical picture in end stage, widely disseminated disease. Only 7 cases of brain metastases from bladder carcinoma existed when the literature was reviewed by Leadbetter and Colston in 1937, including their own case report. 13 The immediate cause of death was the brain lesion in 6 of these 7 cases, and the last patient apparently died of uremia. In 1959 Fetter and associates summarized the findings of 12 large autopsy series reported between 1933 and 1958, including more than 13,000 patients with bladder carcinoma, with the specific purpose of defining sites of metastases. 14 They made no mention of brain metastases. In 1960 Ross and Newall reported on 2 patients who died of brain metastases from primary transitional cell carcinoma of the bladder. 15 Three major groups have published their findings in regard to metastatic transitional cell carcinoma of the bladder. Whitmore and associates reported their experience from 1949 to 1971, and they found only 5 patients in whom brain metastases developed after radical cystectomy. 16 Babaian and associates found 6 cases with brain metastases between 1944 and
BRAIN METASTASES FROM TRANSITIONAL CELL CARCINOMA OF BLADDER
823
FIG. 3. Case 4. A, contrast CT scan of brain with transverse section through posterior fossa shows ring enhancing mass lesion replacing left cerebellar hemisphere. B, magnetic resonance imaging scan of approximately same anatomical level for comparison demonstrates better extent of edema surrounding tumor.
I
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I1: Ji
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II
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1977. 17 From 1967 to 1977 Goldman and associates found 3 cases of brain metastases from bladder carcinoma. 18 In a German autopsy series Hust and Pfitzer identified 3 further cases of transitional cell carcinoma of the bladder metastatic to the central nervous system between 1977 and 1979. 19 Since 1980, however, 19 detailed cases of bladder transitional cell carcinoma metastatic to the brain have been reported.1-9 To these we add our 4 cases for a total of 23 cases. In addition, recent reports have presented at least 3 patients with transitional cell carcinoma of the prostate and a patient with transitional cell carcinoma of the renal pelvis with documented brain metastases.9- 11 It is notable that 3 of our 4 patients, as well as a significant proportion of the recent cases, presented with central nervous system involvement after treatment with systemic cisplatinbased combination chemotherapy. In our first 3 patients who received cisplatin, methotrexate and vinblastine an isolated brain metastasis was the first site of recurrence. Our fourth patient is highly unusual in that he also presented with an isolated brain lesion as the first evidence of metastasis but pelvic lymphadenectomy had been negative for tumor at cystectomy and he had never received chemotherapy. In all of our patients effective local control of the primary tumor had been achieved after radical surgery for high grade, high stage disease. The interval between resection and presentation with intracranial disease ranged from 1 to 20 months. The brain metastases in cases 2 to 4 were treated aggressively with external beam radiation therapy and in 2 cases this was combined with surgical resection. All patients tolerated this treatment well and neurological dysfunction resolved with therapy. Although all patients died only 3 deaths were a result of metastatic transitional cell carcinoma and only 2 were a direct result of brain metastases. Several explanations have been offered for the apparently increasing incidence of transitional cell carcinoma metastases to the brain described in the recent literature. 6 - 11 • 20 These include the increasingly aggressive approach to high grade, high stage cancers with combined therapy, consisting of radiation, radical surgery and combination chemotherapy regimens, resulting in improved local control and an over-all increase seen in late metastases to various anatomical sites in survivors. In this regard the use of systemic chemotherapy in particular may achieve control of tumor in most body sites but it may fail to treat central nervous system micrometastases owing to the blood-brain barrier, the brain acting as a sanctuary for residual tumor. In effect, the pattern of recurrence appears to be altered by chemotherapeutic intervention. Although the numbers of patients involved do not as yet suggest the need for central
nervous system prophylaxis, they do mandate careful attention to and thorough diagnostic evaluation of any neurological findings in these patients. There is evidence from our experience and others7·9· 11 that aggressive intervention, especially for solitary transitional cell carcinoma brain metastases, can provide significant symptomatic improvement and may prolong survival. REFERENCES
1. Findler, G., Feinsod, M., Lijovetzky, G. and Hadani, M.: Transient global amnesia associated with a single metastasis in the nondominant hemisphere. Case report. J. Neurosurg., 58: 303, 1983. 2. Oliver, F., Llopis, B., Guillen, M., Mompo, J. A. and Jimenez Cruz, J. F.: Solitary cerebral metastasis of transitional carcinoma of the bladder: apropos of a case. Arch. Esp. Urol., 37: 533, 1984. 3. Giannone, L., Hainsworth, J. D., Wolff, S. N., Johnson, D. H., Hande, K. R., Grosh, W., Porter, L. and Greco, F. A.: Combination intraventricular chemotherapy with methotrexate (MTX), thio-tepa, and cytosine arabinoside (Ara-C) for neoplastic meningitis. Proc. Amer. Soc. Clin. Oncol., 4: 54, abstract C205, 1985. 4. Davis, R. P., Spigelman, M. K., Zappulla, R. A., Sacher, M. and Strauchen, J. A.: Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature. Neurosurgery, 18: 622, 1986. 5. Hamaguchi, T., Hamami, G., Kamidono, S., Umezu, K., Nakamura, A. and Watanabe, M.: A case of bladder tumor with brain metastasis. Hinyokika Kiyo., 32: 1524, 1986. 6. Steinfeld, A. D. and Zelefsky, M.: Brain metastases from carcinoma of bladder. Urology, 29: 375, 1987. 7. Chan, R. C. and Steinbok, M. B.: Solitary cerebral metastasis: the effect of craniotomy on the quality and the duration of survival. Neurosurgery, 11: 254, 1982. 8. Mandell, S., Wernz, J., Morales, P., Weinberg, H. and Steinfeld, A.: Carcinomatous meningitis from transitional cell carcinoma of bladder. Urology, 25: 520, 1985. 9. Bloch, J. L., Nieh, P. T. and Walzak, M. P.: Brain metastases from transitional cell carcinoma. J. Urol., 137: 97, 1987. 10. Taylor, H. G. and Blom, J.: Transitional cell carcinoma of the prostate: response to treatment with adriamycin and cis-platinum. Cancer, 51: 1800, 1983. 11. Dexeus, F. H., Logothetis, C. J., Samuels, M. L., Ayala, A. G. and Hossan, E.: Complete responses in metastatic transitional cell carcinoma of the prostate with cisplatin regimens. J. Urol., 137: 122, 1987. 12. Harker, W. G., Meyers, F. J., Freiha, F. S., Palmer, J.M., Shortliffe, L. D., Hannigan, J. F., McWhirter, K. M. and Torti, F. M.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract: a Northern California Oncology Group study. J. Clin. Oncol., 3: 1463, 1985.
824
KABALIN, FREIHA AND TORTI
13. Leadbetter, W. F. and Colston, J. A. C.: Brain metastasis in carcinoma of the bladder. J. Urol., 38: 267, 1937. 14. Fetter, T. R., Bogaev, J. H., McCuskey, B. and Seres, J. L.: Carcinoma of the bladder: sites of metastases. J. Urol., 81: 746, 1959. 15. Ross, J. A. and Newall, J.: Unusual metastases in bladder carcinoma. J. Roy. Coll. Surg. Edinb., 6: 51, 1960. 16. Whitmore, W. F., Jr., Batata, M. A., Ghoneim, M. A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. 17. Babaian, R. J., Johnson, D. E., Llamas, L. and Ayala, A. G.: Metastases from transitional cell carcinoma of urinary bladder. Urology, 16: 142, 1980. 18. Goldman, S. M., Fajardo, A. A., Naraval, R. C. and Madewell, J. E.: Metastatic transitional cell carcinoma from the bladder: radiographic manifestations. Amer. J. Roentgen., 132: 419, 1979. 19. Hust, M. H. and Pfitzer, P.: Cerebrospinal fluid and metastasis of transitional cell carcinoma of the bladder. Acta Cytol., 26: 217, 1982. 20. Whitmore, W. F., Jr.: Editorial comment. J. Urol., 137: 125, 1987.
allow for earlier diagnosis than had been heretofore possible. Nonetheless, the observations of the authors are intriguing, and persistent careful observation of patterns of recurrence appears to be warranted as larger numbers of patients with transitional cell cancers are exposed to chemotherapy. The early promise of effective cytotoxic therapy in transitional cell carcinoma needs to be examined in prospective controlled trials wherein high risk patients are randomized to receive or not to receive adjunctive systemic therapy in addition to standard local surgical and radiotherapeutic approaches. Studies are ongoing. Without more data central nervous system prophylaxis with radiation is not indicated but certainly for the occasional patient in whom brain metastases develop radiation therapy may be an effective palliative treatment, reserving consideration of surgical resection for those with solitary lesions in the absence of progressive systemic metastases. Continuing studies of larger numbers of patients achieving long-term survival will determine if prophylactic brain treatments should be tested and which subpopulations of patients are at highest risk of central nervous involvement. Merrill Kies Department of Medicine Northwestern University School of Medicine Chicago, Illinois
EDITORIAL COMMENTS
1. Sternberg, C. N., Yagoda, A., Scher, H. I., Watson, R. C., Ahmed, T., Weiselberg, L. R., Geller, N., Hollander, P. S., Herr, H. W., Sogani, P. C., Morse, M. J. and Whitmore, W. F.: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J. Urol., 133: 403, 1985. 2. Hrushesky, W. J.M., Roemeling, R. V., Wood, P.A., Langevin, T. R., Lange, P. and Farley, E.: High-dose intensity systemic therapy for metastatic bladder cancer. J. Clin. Oncol., 5: 450, 1987. 3. Yagoda, A.: Chemotherapy of urothelial tract tumors. Cancer, suppl., 60: 574, 1987.
This article is timely because we appear to be moving to a new period of better treatment of transitional cell carcinoma of the bladder. In 1988 there are estimated to be 46,000 new cases of bladder cancer and 11,000 deaths. The majority of survivors have been those with superficial bladder cancers who can be treated effectively with transurethral fulguration or intravesical cytotoxic and immunological agents. In contrast, the majority of patients with invasive transitional cell carcinoma have fared less well despite radical cystectomy with or without adjunctive radiation. For patients with lymph node involvement the 5year survival has been poor (less than 10 per cent) with the vast majority of patients dying of metastatic disease. What has changed is that pilot studies of cisplatin-based combination chemotherapy show great promise for the treatment of metastatic disease, so much so that transitional cell carcinoma of the urothelium is now considered a tumor responsive to chemotherapy. Partial tumor regressions have ranged from 20 to, 40 per cent and more importantly complete disease remissions have been obtained in 25 to 40 per cent of the patients (reference 12 in article). 1• 2 Yagoda has used methotrexate, vinblastine, doxorubicin and cisplatin in patients with advanced disease, and patients with pathologically confirmed clinical complete disease remission had a median survival in excess of 32 months. 3 These advances have prompted more systematic observations of the quality of disease remission and patterns of relapse, and they have spurred attempts to devise innovative treatment strategies to prevent tumor recurrence. Recognition of brain metastases may have increased because chemotherapy helps to control systemic disease and patients live longer. The 4 patients in this series are notable because isolated brain metastases developed as the first site of recurrence, local control of the primary tumor was achieved and the time to tumor recurrence ranged up to 20 months. Three patients have been described with solitary brain lesions in the setting of widespread metastatic disease from primary bladder cancer (references 6 and 9 in article). This will likely be the more common pattern. There is concern that with the emerging use of effective systemic chemotherapy and prolongation of survival there may be a failure to treat central nervous system metastases owing to poor drug penetration with the result that the brain becomes a sanctuary for residual tumor. This may be so but we must consider the small number of cases with well documented brain metastases reported to date and an increasing awareness by managing physicians of the potential for central nervous system metastases to occur. Moreover, imaging techniques certainly
The authors present 4 cases of central nervous metastases following treatment of transitional cell carcinoma of the bladder. In cases 1 and 3 an isolated brain metastasis was the first sign of recurrence. In case 2 brain metastases may well have been the solitary metastatic site but no CT scan of the abdomen was done at the time the patient presented with the neurological symptoms and a large abdominal mass was noted 3 months later. Of 83 cases from Memorial Sloan-Kettering Cancer Center central nervous system metastases developed in 10 (12 per cent), including 6 relapses in patients thought to have had complete clinical (3) or pathological (3) remissions. 1 No tumor was in the bladder specimen or lymph nodes at the time of removal of the primary tumor. Of the remaining 4 partial responders relapse occurred in the central nervous system. The median time to development of central nervous disease for the entire group was 11 months (range 6 to 42 months) and survival from the time of diagnosis of central nervous system disease averaged 2 months (range 1 to 21 months). As the authors have indicated effective control of other metastatic sites may increase patient survival to the point that a higher percentage of central nervous system relapse may be anticipated. Our own experience plus the references cited by the authors would indicate that although treatment of brain metastases may significantly palliate neu rological symptoms, there is little evidence that such treatment prolongs survival and the outlook for patients with demonstrated central nervous relapse remains bleak. William R. Fair Urology Service Memorial Sloan-Kettering Cancer Center New York, New York 1. Sternberg, C. N., Yagoda, A., Scher, H. I., Watson, R. C., Herr, H. W., Morse, M. J., Sogani, P. C., Vaughan, E. D., Jr., Bander, N., Weiselberg, L. R., Geller, N., Hollander, P. S., Lipperman, R., Fair, W.R. and Whitmore, W. F., Jr.: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J. Urol., 139: 461, 1988.
Vol. 140, October Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1988 by The Williams & Wilkins Co.
BRAIN METASTASES FROM TRANSITIONAL CELL CARCINOMA OF THE BLADDER JOHN N. KABALIN, FUAD S. FREIHA AND FRANK M. TORTI From the Divisions of Urology and Oncology, and the Stanford GU Oncology Clinic, Stanford University Medical Center and Palo Alto Veterans Administration Medical Center, Stanford, California
ABSTRACT
We present our experience with 4 patients with transitional cell carcinoma of the bladder and brain metastases. In all 4 cases a solitary intracranial metastasis occurred. In 3 patients this represented the first site of recurrent disease following systemic chemotherapy. Aggressive therapy of the brain metastases was instituted in 3 patients, including external beam radiation and in 2 cases surgical resection. Although all patients died only 3 died as a result of metastatic transitional cell carcinoma, including 2 who died as a direct result of intracranial disease. A review of the literature suggests an increasing incidence of brain metastases from transitional cell carcinoma of the bladder with the advent of more aggressive therapy for bladder cancer, which includes radical surgery for high stage disease and combination chemotherapy. Aggressive intervention for solitary brain metastases from transitional cell carcinoma can relieve neurological dysfunction and may prolong survival. (J. Ural., 140: 820-824, 1988) Common sites for metastases from transitional cell carcinoma of the bladder include lymph nodes, lung, bone, liver and adrenal gland. The recent literature suggests an increasing incidence of central nervous system involvement by transitional cell carcinoma metastases 1- 12 associated with the expanding use of systemic combination chemotherapy in the treatment of patients with advanced disease. We describe 4 patients seen by us since 1983 with transitional cell carcinoma metastases to the brain. All lesions were solitary, and they involved the cerebrum in 2 cases and the cerebellum in 2 (see table). In 3 patients metastasis to the brain developed after treatment with cisplatin, methotrexate and vinblastine combination chemotherapy. 12 CASE REPORTS
Case 1. A. M., a 62-year-old woman, presented in March 1982 with complaints of progressive urinary frequency and dysuria during the preceding several months and the new onset of gross hematuria. A large, fixed anterior mass was palpated on pelvic examination. Excretory urography showed moderate bilateral hydronephrosis with ureterectasis to the level of the ureterovesical junctions. Serum creatinine was 1.9 mg./dl. (normal 0.5 to 1.4). Malignant cells were found in a urine cytology specimen. Cystoscopy revealed no distinct tumor but diffuse edema and erythema of the bladder were noted. Neither ureteral orifice could be seen. Bladder biopsies showed grade IV transitional cell carcinoma. A computerized tomography (CT) scan of the abdomen and pelvis showed a large mass involving the bladder dome and invading the uterus posteriorly and the abdominal wall anteriorly. No evidence of intra-abdominal lymphadenopathy or metastasis was seen and a chest x-ray also showed no evidence of metastatic disease. Bipedal lymphangiography was normal. Three cycles of cisplatin, methotrexate and vinblastine chemotherapy were administered followed by 4,500 rad external beam radiation to the pelvis. By July pelvic examination revealed no palpable mass. Repeat CT scan showed resolution of the hydronephrosis bilaterally and a marked reduction in the size of the bladder mass_ Cystoscopy and bladder biopsy confirmed persistent grade III transitional cell carcinoma. A fourth Accepted for publication January 28, 1988.
cycle of cisplatin, methotrexate and vinblastine was administered and another CT scan was obtained in September, which showed only anterior bladder wall thickening. An abdominal CT scan and a chest x-ray continued to show no evidence of lymphadenopathy or metastasis. Serum creatinine was 1. 7. Surgical exploration on October 7 confirmed these findings and anterior pelvic exenteration with ileal loop urinary diversion was performed. Pathological examination showed multifocal grade III transitional cell carcinoma infiltrating the submucosa but no evidence of muscle invasion. The perivesical tissues and lymph nodes were not involved by tumor. Initially the patient did well after cystectomy and she was discharged from the hospital 14 days postoperatively. In February 1983 she was seen for complaints of left hip pain but otherwise she was well. Plain film x-rays and a nuclear bone scan showed no abnormalities. On March 6 the patient was hospitalized because of nausea, vomiting, dehydration and increasing confusion several days in duration. She experienced some difficulty with ambulation but no focal neurological abnormality was identified. Despite intravenous rehydration she became comatose within 24 hours after hospitalization and she died shortly thereafter. Postmortem examination showed a single 3 X 2 X 2 cm. transitional cell carcinoma metastasis in the right cerebellar hemisphere and evidence of brainstem herniation. No other sites of residual disease or metastasis were present in the pelvis, abdomen or chest. Case 2. A. S., a 59-year-old man, presented with total gross painless hematuria in October 1982. Cystoscopy revealed extensive bladder tumor and transurethral resection showed grade IV transitional cell carcinoma with muscle invasion. An IVP demonstrated normal upper tracts bilaterally. Although a chest x-ray, bone scan and CT scan of the abdomen showed no evidence of metastases, exploration in November revealed gross bilateral pelvic lymphadenopathy and biopsies were positive for metastatic transitional cell carcinoma. Cystoprostatectomy with ileal loop diversion was performed with no attempt at lymphadenectomy. Pathological examination of this resection showed grade III to IV transitional cell carcinoma with muscle invasion and carcinoma in situ extending into the prostatic urethra. A single small focus of prostatic adenocarcinoma also was present.
820
on~
BRAIN Iv1E'TASTASES FROM TRANSI'HONAL CELL CARCINOi\iIA OF BLADDER
OLI.
Sumniary of 4 patients with brain, rnetastases frorn transitional cell carcinorn,a of the b!,{1dde? Case 1
Pt. age
62
Surgical pathology
Multifocal, grade III transitional cell Ca A2 4 cycles cisplatin, methotrexate and vinblastine 4,500
Surgical stage Chemotherapy
Local radiotherapy (rad) Interval between surgical resection and presentation with brain metastasis (mos.) Site of brain metastasis Treatment of brain metastasis Interval between presentation with brain metastasis and death Cause of death
Case 3
Case 2
Case 4
59 66 74 Grade III-IV transitional cell Ca with muscle invasion and presence of focal Ca in situ
Dl
Dl
6 cycles cisplatin, methotrexate and vinblastine None 20
6 cycles cisplatin, methotrexate and vinblastine 2,000 7
Frontal lobe 5,500 rad
Days
Lt. frontoparietal lobe Resection and 3,000 rad 4 mos.
4 mos.
Cerebellum Resection and 4,000 rad 4 mos.
Brain metastasis
Abdominal metastases
Sepsis
Brain metastasis
5
Cerebellum None
Beginning in January 1983 the patient received a total of 6 cycles of cisplatin, methotrexate and vinblastine chemotherapy. A followup CT scan of the abdomen and pelvis in November showed a persistent 5 X 3 cm. lymph node mass in the area of the right common iliac chain. In December laparotomy was performed and the right iliac mass was resected but no other evidence of intra-abdominal disease was found. Pathological examination of the mass showed fibrosis and no evidence of tumor. The patient was well until July 1984 when he presented with complaints of left temporal headaches, garbled speech and mild right hemiparesis. A CT scan of the brain showed a 3 X 3 cm. left frontoparietal mass (fig. 1). A chest x-ray and bone scan showed no evidence of other metastatic disease. Craniotomy and resection of the mass confirmed metastatic transitional cell carcinoma. The patient received 3,000 rad whole brain external beam radiation postoperatively and all neurological symptoms resolved. In October he returned with small bowel obstruction and exploratmy laparotomy revealed a single large mass involving the ileum and omentum. The mass, omentum and a segment of ileum were resected and primary enteroenterostomy was performed. Pathological examination revealed metastatic transitional cell carcinoma. The patient was discharged from the hospital in good condition but within a month a recurrent abdominal mass was easily palpable and he had become severely cachectic. He died within 48 hours of rehospitalization for terminal care. Case 3. M. R., a 66-year-old man, first presented with total gross hematuria associated with vague pelvic discomfort in June 1985. Cystoscopy showed a large tumor at the bladder dome and transurethral resection was performed. Pathological report was grade III to IV transitional cell carcinoma with muscle invasion and carcinoma in situ. The patient received 2,000 rad external beam radiation followed by partial cystectomy in August. A single right external iliac node contained metastatic tumor, and tumor also was present at the surgical margin of the bladder specimen. Between September and December he received 4 cycles of cisplatin, methotrexate and vinblastine combination chemotherapy. A chest x-ray, bone scan and CT scan of the abdomen and pelvis failed to demonstrate definite evidence of metastases and in February 1986 radical cystectomy with a Camey ileal bladder substitution was performed. The resected specimen showed no evidence of residual transitional cell carcinoma in the bladder or lymph nodes, including the periaortic nodes. There were several small foci of prostatic adenocarcinoma (Gleason 3+3) confined to the prostate gland. Two further
C None
None 1
FIG. L Case 2. Contrast CT scan of brain shows left frontoparietal mass with ring enhancement and central areas of cystic necrosis.
cycles of cisplatin, methotrexate and vinblastine therapy were administered postoperatively. In June the patient first complained of right rib pain. A bone scan in September showed increased uptake in the right sixth rib. Biopsy revealed atypical cells but no definite evidence of malignancy. Prostatic acid phosphatase level was normaL The patient was noticed by the family to be progressively disoriented and experiencing difficulty especially with short-term memory loss. He had regained continence after the Camey procedure but he now was incontinent of urine and he complained of frontal headaches. A CT scan of the head showed a 4 x 4 cm. midline frontal brain mass (fig. 2, A). Stereotactic needle biopsy was positive for metastatic transitional cell carcinoma of high grade. The patient was treated with 5,500 rad whole brain external beam radiation, as well as 2,000 rad directed to the right sixth rib. Mental status returned to normal and a CT scan in November showed reduction in the size of the brain lesion (fig. 2, B). A chest x-ray remained clear. In December the patient presented with a new left lower quadrant fistula draining through the site of the previous Penrose drain placement for cystectomy. The drainage ap-
822
KABALIN, FREIHA AND TORTI
FIG. 2. Case 3. A, contrast CT scan of brain shows enhancing frontal mass almost in midline. There is extensive area of cerebral edema surrounding tumor. B, repeat CT scan after 5,500 rad external beam radiation reveals marked diminution in size of lesion.
peared to consist of liquid stool and urine. A fistulogram confirmed communication with the Camey ileal bladder but a loopogram, barium enema and small bowel series failed to demonstrate a communication with the gastrointestinal tract. He was managed conservatively with Foley catheter drainage of the Camey loop, and the fistula closed spontaneously. The patient returned in January 1987 with severe diarrhea several days in duration, the fistula was reopened and draining, and he appeared septic. Serum potassium was 1.9 mEq./1. (normal 3.5 to 5.3) with a serum bicarbonate of 15 mEq./1. (normal 24 to 31) and a creatinine of 1.2. Prostate specific antigen level was 0.0 ng./ml. (normal 0.0 to 2.5). He progressed rapidly into septic shock. Cultures of the urine, fistula drainage and blood yielded large numbers of Escherichia coli. Despite vigorous attempts at resuscitation the patient died within 72 hours of hospitalization of overwhelming sepsis. Postmortem examination showed no evidence of persistent or recurrent tumor in the abdomen or pelvis. Case 4. B. M., a 74-year-old man, first presented with total gross painless hematuria in 1979. He had undergone transurethral resection of a bladder tumor in Iran and the pathological report was unavailable. The patient was followed with no evidence of recurrence until October 1986 when he presented with hematuria and irritative bladder symptoms. Multiple papillary tumors were found at cystoscopy and transurethral resection revealed areas of grade IV transitional cell carcinoma with focal muscle invasion. He was referred to our hospital, and a chest x-ray and CT scan of the abdomen and pelvis showed no evidence of metastases. In January 1987 radical cystectomy with a hemi-Kock ileal bladder substitution was performed. Pathological examination revealed multiple grade III to IV papillary transitional cell carcinoma lesions with muscle invasion and extension into perivesical fat. Multifocal carcinoma in situ also was present. All lymph nodes and surgical margins were clear of tumor. The patient was rehospitalized in February for complaints of nausea and dizziness with no focal neurological findings. He was initially treated for the diagnosis of viral labyrinthitis. Shortly after hospitalization he suffered a pulmonary embolus requiring systemic anticoagulation. The nausea and vertigo did not improve and he began to experience severe headaches. A CT scan (fig. 3, A) and magnetic resonance imaging (fig. 3, B) of the brain revealed a 3 cm. left cerebellar mass with obstruction of the fourth ventricle. Anticoagulant therapy was discontinued and resection of the left cerebellar hemisphere was performed. Pathological examination revealed poorly differen-
tiated metastatic transitional cell carcinoma. The patient did well after this procedure and he was discharged from the hospital after adequate oral anticoagulation with sodium warfarin. Postoperative brain radiation was recommended but refused by the patient. In April he was rehospitalized with oliguria, a creatinine of 4.3 and a serum potassium of 6.4. Ultrasound showed bilateral hydronephrosis and bilateral percutaneous nephrostomy tubes were placed. Serum creatinine and electrolytes normalized. Antegrade nephrostograms demonstrated bilateral distal ureteral obstruction at the anastomoses with the hemi-Kock pouch. A chest x-ray remained clear. A repeat CT scan of the brain showed recurrence of the cerebellar tumor. With his consent the patient received 3,000 rad external beam radiation to the whole brain and 4,000 rad to the posterior fossa through June. Within a week of completing the radiation therapy he returned with increasing lethargy, weakness and dehydration secondary to diminishing oral intake. The deterioration was believed to be owing to progression of the intracranial metastatic tumor. He and his family refused further diagnostic or therapeutic intervention other than intravenous hydration. He became comatose and died 9 days after hospitalization. Postmortem examination was refused. DISCUSSION
Metastasis to the brain from transitional cell carcinoma of the bladder is unusual. It has rarely been encountered as part of the clinical picture in end stage, widely disseminated disease. Only 7 cases of brain metastases from bladder carcinoma existed when the literature was reviewed by Leadbetter and Colston in 1937, including their own case report. 13 The immediate cause of death was the brain lesion in 6 of these 7 cases, and the last patient apparently died of uremia. In 1959 Fetter and associates summarized the findings of 12 large autopsy series reported between 1933 and 1958, including more than 13,000 patients with bladder carcinoma, with the specific purpose of defining sites of metastases. 14 They made no mention of brain metastases. In 1960 Ross and Newall reported on 2 patients who died of brain metastases from primary transitional cell carcinoma of the bladder. 15 Three major groups have published their findings in regard to metastatic transitional cell carcinoma of the bladder. Whitmore and associates reported their experience from 1949 to 1971, and they found only 5 patients in whom brain metastases developed after radical cystectomy. 16 Babaian and associates found 6 cases with brain metastases between 1944 and
BRAIN METASTASES FROM TRANSITIONAL CELL CARCINOMA OF BLADDER
823
FIG. 3. Case 4. A, contrast CT scan of brain with transverse section through posterior fossa shows ring enhancing mass lesion replacing left cerebellar hemisphere. B, magnetic resonance imaging scan of approximately same anatomical level for comparison demonstrates better extent of edema surrounding tumor.
I
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l: 11 j) j
I1: Ji
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1977. 17 From 1967 to 1977 Goldman and associates found 3 cases of brain metastases from bladder carcinoma. 18 In a German autopsy series Hust and Pfitzer identified 3 further cases of transitional cell carcinoma of the bladder metastatic to the central nervous system between 1977 and 1979. 19 Since 1980, however, 19 detailed cases of bladder transitional cell carcinoma metastatic to the brain have been reported.1-9 To these we add our 4 cases for a total of 23 cases. In addition, recent reports have presented at least 3 patients with transitional cell carcinoma of the prostate and a patient with transitional cell carcinoma of the renal pelvis with documented brain metastases.9- 11 It is notable that 3 of our 4 patients, as well as a significant proportion of the recent cases, presented with central nervous system involvement after treatment with systemic cisplatinbased combination chemotherapy. In our first 3 patients who received cisplatin, methotrexate and vinblastine an isolated brain metastasis was the first site of recurrence. Our fourth patient is highly unusual in that he also presented with an isolated brain lesion as the first evidence of metastasis but pelvic lymphadenectomy had been negative for tumor at cystectomy and he had never received chemotherapy. In all of our patients effective local control of the primary tumor had been achieved after radical surgery for high grade, high stage disease. The interval between resection and presentation with intracranial disease ranged from 1 to 20 months. The brain metastases in cases 2 to 4 were treated aggressively with external beam radiation therapy and in 2 cases this was combined with surgical resection. All patients tolerated this treatment well and neurological dysfunction resolved with therapy. Although all patients died only 3 deaths were a result of metastatic transitional cell carcinoma and only 2 were a direct result of brain metastases. Several explanations have been offered for the apparently increasing incidence of transitional cell carcinoma metastases to the brain described in the recent literature. 6 - 11 • 20 These include the increasingly aggressive approach to high grade, high stage cancers with combined therapy, consisting of radiation, radical surgery and combination chemotherapy regimens, resulting in improved local control and an over-all increase seen in late metastases to various anatomical sites in survivors. In this regard the use of systemic chemotherapy in particular may achieve control of tumor in most body sites but it may fail to treat central nervous system micrometastases owing to the blood-brain barrier, the brain acting as a sanctuary for residual tumor. In effect, the pattern of recurrence appears to be altered by chemotherapeutic intervention. Although the numbers of patients involved do not as yet suggest the need for central
nervous system prophylaxis, they do mandate careful attention to and thorough diagnostic evaluation of any neurological findings in these patients. There is evidence from our experience and others7·9· 11 that aggressive intervention, especially for solitary transitional cell carcinoma brain metastases, can provide significant symptomatic improvement and may prolong survival. REFERENCES
1. Findler, G., Feinsod, M., Lijovetzky, G. and Hadani, M.: Transient global amnesia associated with a single metastasis in the nondominant hemisphere. Case report. J. Neurosurg., 58: 303, 1983. 2. Oliver, F., Llopis, B., Guillen, M., Mompo, J. A. and Jimenez Cruz, J. F.: Solitary cerebral metastasis of transitional carcinoma of the bladder: apropos of a case. Arch. Esp. Urol., 37: 533, 1984. 3. Giannone, L., Hainsworth, J. D., Wolff, S. N., Johnson, D. H., Hande, K. R., Grosh, W., Porter, L. and Greco, F. A.: Combination intraventricular chemotherapy with methotrexate (MTX), thio-tepa, and cytosine arabinoside (Ara-C) for neoplastic meningitis. Proc. Amer. Soc. Clin. Oncol., 4: 54, abstract C205, 1985. 4. Davis, R. P., Spigelman, M. K., Zappulla, R. A., Sacher, M. and Strauchen, J. A.: Isolated central nervous system metastasis from transitional cell carcinoma of the bladder: report of a case and review of the literature. Neurosurgery, 18: 622, 1986. 5. Hamaguchi, T., Hamami, G., Kamidono, S., Umezu, K., Nakamura, A. and Watanabe, M.: A case of bladder tumor with brain metastasis. Hinyokika Kiyo., 32: 1524, 1986. 6. Steinfeld, A. D. and Zelefsky, M.: Brain metastases from carcinoma of bladder. Urology, 29: 375, 1987. 7. Chan, R. C. and Steinbok, M. B.: Solitary cerebral metastasis: the effect of craniotomy on the quality and the duration of survival. Neurosurgery, 11: 254, 1982. 8. Mandell, S., Wernz, J., Morales, P., Weinberg, H. and Steinfeld, A.: Carcinomatous meningitis from transitional cell carcinoma of bladder. Urology, 25: 520, 1985. 9. Bloch, J. L., Nieh, P. T. and Walzak, M. P.: Brain metastases from transitional cell carcinoma. J. Urol., 137: 97, 1987. 10. Taylor, H. G. and Blom, J.: Transitional cell carcinoma of the prostate: response to treatment with adriamycin and cis-platinum. Cancer, 51: 1800, 1983. 11. Dexeus, F. H., Logothetis, C. J., Samuels, M. L., Ayala, A. G. and Hossan, E.: Complete responses in metastatic transitional cell carcinoma of the prostate with cisplatin regimens. J. Urol., 137: 122, 1987. 12. Harker, W. G., Meyers, F. J., Freiha, F. S., Palmer, J.M., Shortliffe, L. D., Hannigan, J. F., McWhirter, K. M. and Torti, F. M.: Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract: a Northern California Oncology Group study. J. Clin. Oncol., 3: 1463, 1985.
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KABALIN, FREIHA AND TORTI
13. Leadbetter, W. F. and Colston, J. A. C.: Brain metastasis in carcinoma of the bladder. J. Urol., 38: 267, 1937. 14. Fetter, T. R., Bogaev, J. H., McCuskey, B. and Seres, J. L.: Carcinoma of the bladder: sites of metastases. J. Urol., 81: 746, 1959. 15. Ross, J. A. and Newall, J.: Unusual metastases in bladder carcinoma. J. Roy. Coll. Surg. Edinb., 6: 51, 1960. 16. Whitmore, W. F., Jr., Batata, M. A., Ghoneim, M. A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. 17. Babaian, R. J., Johnson, D. E., Llamas, L. and Ayala, A. G.: Metastases from transitional cell carcinoma of urinary bladder. Urology, 16: 142, 1980. 18. Goldman, S. M., Fajardo, A. A., Naraval, R. C. and Madewell, J. E.: Metastatic transitional cell carcinoma from the bladder: radiographic manifestations. Amer. J. Roentgen., 132: 419, 1979. 19. Hust, M. H. and Pfitzer, P.: Cerebrospinal fluid and metastasis of transitional cell carcinoma of the bladder. Acta Cytol., 26: 217, 1982. 20. Whitmore, W. F., Jr.: Editorial comment. J. Urol., 137: 125, 1987.
allow for earlier diagnosis than had been heretofore possible. Nonetheless, the observations of the authors are intriguing, and persistent careful observation of patterns of recurrence appears to be warranted as larger numbers of patients with transitional cell cancers are exposed to chemotherapy. The early promise of effective cytotoxic therapy in transitional cell carcinoma needs to be examined in prospective controlled trials wherein high risk patients are randomized to receive or not to receive adjunctive systemic therapy in addition to standard local surgical and radiotherapeutic approaches. Studies are ongoing. Without more data central nervous system prophylaxis with radiation is not indicated but certainly for the occasional patient in whom brain metastases develop radiation therapy may be an effective palliative treatment, reserving consideration of surgical resection for those with solitary lesions in the absence of progressive systemic metastases. Continuing studies of larger numbers of patients achieving long-term survival will determine if prophylactic brain treatments should be tested and which subpopulations of patients are at highest risk of central nervous involvement. Merrill Kies Department of Medicine Northwestern University School of Medicine Chicago, Illinois
EDITORIAL COMMENTS
1. Sternberg, C. N., Yagoda, A., Scher, H. I., Watson, R. C., Ahmed, T., Weiselberg, L. R., Geller, N., Hollander, P. S., Herr, H. W., Sogani, P. C., Morse, M. J. and Whitmore, W. F.: Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J. Urol., 133: 403, 1985. 2. Hrushesky, W. J.M., Roemeling, R. V., Wood, P.A., Langevin, T. R., Lange, P. and Farley, E.: High-dose intensity systemic therapy for metastatic bladder cancer. J. Clin. Oncol., 5: 450, 1987. 3. Yagoda, A.: Chemotherapy of urothelial tract tumors. Cancer, suppl., 60: 574, 1987.
This article is timely because we appear to be moving to a new period of better treatment of transitional cell carcinoma of the bladder. In 1988 there are estimated to be 46,000 new cases of bladder cancer and 11,000 deaths. The majority of survivors have been those with superficial bladder cancers who can be treated effectively with transurethral fulguration or intravesical cytotoxic and immunological agents. In contrast, the majority of patients with invasive transitional cell carcinoma have fared less well despite radical cystectomy with or without adjunctive radiation. For patients with lymph node involvement the 5year survival has been poor (less than 10 per cent) with the vast majority of patients dying of metastatic disease. What has changed is that pilot studies of cisplatin-based combination chemotherapy show great promise for the treatment of metastatic disease, so much so that transitional cell carcinoma of the urothelium is now considered a tumor responsive to chemotherapy. Partial tumor regressions have ranged from 20 to, 40 per cent and more importantly complete disease remissions have been obtained in 25 to 40 per cent of the patients (reference 12 in article). 1• 2 Yagoda has used methotrexate, vinblastine, doxorubicin and cisplatin in patients with advanced disease, and patients with pathologically confirmed clinical complete disease remission had a median survival in excess of 32 months. 3 These advances have prompted more systematic observations of the quality of disease remission and patterns of relapse, and they have spurred attempts to devise innovative treatment strategies to prevent tumor recurrence. Recognition of brain metastases may have increased because chemotherapy helps to control systemic disease and patients live longer. The 4 patients in this series are notable because isolated brain metastases developed as the first site of recurrence, local control of the primary tumor was achieved and the time to tumor recurrence ranged up to 20 months. Three patients have been described with solitary brain lesions in the setting of widespread metastatic disease from primary bladder cancer (references 6 and 9 in article). This will likely be the more common pattern. There is concern that with the emerging use of effective systemic chemotherapy and prolongation of survival there may be a failure to treat central nervous system metastases owing to poor drug penetration with the result that the brain becomes a sanctuary for residual tumor. This may be so but we must consider the small number of cases with well documented brain metastases reported to date and an increasing awareness by managing physicians of the potential for central nervous system metastases to occur. Moreover, imaging techniques certainly
The authors present 4 cases of central nervous metastases following treatment of transitional cell carcinoma of the bladder. In cases 1 and 3 an isolated brain metastasis was the first sign of recurrence. In case 2 brain metastases may well have been the solitary metastatic site but no CT scan of the abdomen was done at the time the patient presented with the neurological symptoms and a large abdominal mass was noted 3 months later. Of 83 cases from Memorial Sloan-Kettering Cancer Center central nervous system metastases developed in 10 (12 per cent), including 6 relapses in patients thought to have had complete clinical (3) or pathological (3) remissions. 1 No tumor was in the bladder specimen or lymph nodes at the time of removal of the primary tumor. Of the remaining 4 partial responders relapse occurred in the central nervous system. The median time to development of central nervous disease for the entire group was 11 months (range 6 to 42 months) and survival from the time of diagnosis of central nervous system disease averaged 2 months (range 1 to 21 months). As the authors have indicated effective control of other metastatic sites may increase patient survival to the point that a higher percentage of central nervous system relapse may be anticipated. Our own experience plus the references cited by the authors would indicate that although treatment of brain metastases may significantly palliate neu rological symptoms, there is little evidence that such treatment prolongs survival and the outlook for patients with demonstrated central nervous relapse remains bleak. William R. Fair Urology Service Memorial Sloan-Kettering Cancer Center New York, New York 1. Sternberg, C. N., Yagoda, A., Scher, H. I., Watson, R. C., Herr, H. W., Morse, M. J., Sogani, P. C., Vaughan, E. D., Jr., Bander, N., Weiselberg, L. R., Geller, N., Hollander, P. S., Lipperman, R., Fair, W.R. and Whitmore, W. F., Jr.: M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for advanced transitional cell carcinoma of the urothelium. J. Urol., 139: 461, 1988.