Brirish J o u r ~ l o f Urology (1990), 65.473477 0 1990 British Journal of Urology

0007- I331/90/0065-0473/$10.00

Treatment of Bladder Carcinoma Using a Germ Cell Chemotherapy Protocol

GRANT WILLIAMS, R. A. COLBECK and S. M. CRAWFORD

Cancer Research Campaign Laboratories, Department of Medical Oncology, Charing Cross Hospital, London

Summary-Elevated levels of circulating P-human chorionic gonadotrophin (P-HCG) are commonly associated with a variety of tumours of germ cell origin. Other carcinomas may possess choriocarcinomatous elements but only rarely have there been reports of transitional cell carcinomas of the bladder associated with raised germ cell tumour markers, possibly because assays are not routinely performed.

We present 3 patients with advanced transitional cell carcinoma of the bladder, 2 with metastatic and 1 with locally invasive disease, who had raised levels of germ cell tumour markers. These patients were therefore treated with combination chemotherapy appropriate to such tumours, with excellent results, as shown by clinical improvement and return to normal of tumour marker levels. Recent reports of the association between bladder carcinoma and ectopic synthesis of 0-HCG are reviewed. It was concluded that the production of P-HCG is probably not rare, but that when it is found, the adoption of an appropriate chemotherapeutic regime may be successful.

I t is well established that increased levels of circulating P-human chorionic gonadotrophin may be associated with a variety of tumours of trophob- lastic origin, in both men and non-pregnant women.

The assay of urinary and serum P-HCG has provided a means of monitoring the progress of treatment in cases of choriocarcinoma and testicu- lar cancer with choriocarcinomatous elements for over 50 years. Other carcinomas may feature choriocarcinomatous elements, including tumours of the stomach (Regan and Cremin, 1960), lung (Dailey and Marcuse, 1969) and oesophagus (McKechnie and Fechner, 1971), but it is unusual for transitional cell carcinoma of the bladder to be associated with elevated serum levels of P-HCG (Kawamura et al., 1978).

By February 1986 only 11 cases of primary choriocarcinoma of the bladder had been reported (Shah et al., 1986) and only 3 documented cases of transitional cell carcinoma with gonadotrophin

Accepted for publication 1 September 1989

secretion (Civantos and Rywlin, 1972 ; Kawamura et al., 1978). However, subsequent immunohisto- chemical investigation of 13 other bladder carci- nomas revealed /?-HCG-like immunoreactivity in 5, which would suggest that this property is not as rare as was previously supposed (Rodenburg et af., 1985).

Indeed, in a review of 104 transitional cell carcinomas of the bladder, using the indirect immunoperoxidase technique, P-HCG production was found in 12 of them, 11 of which were grades 3 and 4 transitional cell tumours (Civantos and Rywlin, 1972).

We present 3 patients with advanced transitional cell carcinoma of the bladder who were found to have elevated levels of tumour markers-P-HCG in all cases, and CEA (carcinoembryonic antigen) and AFP (alphafetoprotein) additionally in 1.

The success of combination chemotherapy in the treatment of anaplastic germ cell tumours and the value of serial tumour marker estimation in assess- ing response prompted the adoption of such a regime, and the results are presented and discussed.

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474 BRITISH JOURNAL OF UROLOGY

Case Reports Case f. A 47-year-old man presented with frank haema- turia. At cystoscopy a transitional cell carcinoma of the bladder was found. Initial staging of the tumour was not available because he was treated with regular cystodiath- ermy. Seventeen months later he complained of abdomi- nal discomfort and had developed ascites. At laparatomy there was widespread intra-abdominal tumour, with no apparent primary source. Biopsy of the omentum showed a poorly differentiated mucus-secreting adenocarcinoma of unknown origin. Further investigation revealed axil- lary lymphadenopathy, bilateral gynaecomastia and ascites. The testes were normal.

After preliminary investigations the serum fi-HCG was found to be raised at 2709 iu/l, CEA raised to 23 pg/ I and AFP to 59 ku/l.

Lumbar puncture showed the CSF to have no malig- nant cells with a fl-HCG level of 20 iu/l and AFP < 2 ku/ I. Ultrasound scan showed a nodule < 1 cm in the right lobe of the liver and a 4-cm mass superior and posterior to the bladder. CT scanning of the thorax and abdomen confirmed the presence of ascites and a right pleural effusion.

The original histological specimens from the bladder were compared with the omental biopsy. The bladder specimen showed fibromuscular fragments infiltrated by a carcinoma composed of eosinophilic pleomorphic cells forming clusters and occasional acinar structures. There were frequent mononuclear tumour giant cells and occasional multinucleated tumour giant cells. Acidophilic hyaline inclusions were present in some cells together with necrosis, focal calcification and diathermy artefact.

The omental tumour showed fibrovascular tissue with tumour similar to that in the first specimen, in which glandular formation was more evident. The appearance of both was of a poorly differentiated invasive transitional cell carcinoma, probably of bladder origin, with metas- tases in the peritoneum.

Because the elevated levels of fl-HCG and AFP suggested that the disseminated tumour had features of germ cell differentiation, the patient was treated with combination chemotherapy appropriate to testicular non- seminomatous germ cell tumours.

In view of his poor state at the start of treatment, the initial treatment was low dose cisplatin 20 mg/m* i.v. and etoposide 100 mg/m? i.v.

This was followed by courses of full dose cisplatin (100 mg/m?) with pre-hydration and etoposide 200 mg/ m? in 250 ml saline over 30 min alternating with OMB:

Day I : vincristine 1 mg/rn? i.v., methotrexate 300 mg/ m? as a 12-h infusion.

Day 2 : bleomycin 15 mg by 24-h infusion; folinic acid rescue started at 24 h (after start of methotrexate) in a dose of 15 mg 12-hourly for 4 doses.

Day 3 : bleomycin I5 mg by 24-h infusion.

These courses were alternated at 10-day intervals. After 3 courses the axillary nodes were not palpable, ascites

disappeared and fl-HCG, CEA and AFP levels dropped rapidly, reaching normal after 8 weeks of chemotherapy (Fig. I) . The chemotherapy was complicated by vomiting and alopecia.

Serial ultrasound scans showed resolution of the bladder mass and C T scanning confirmed the disappear- ance of the ascites and pleural effusion. Sixteen weeks after starting chemotherapy, cystoscopy showed no trace of intravesical tumour. Chemotherapy was completed at 25 weeks and the patient has been followed up at regular intervals. The germ cell tumour markers have continued to remain within normal limits and there is no sign of clinical recurrence, with further cystoscopies remaining normal.

Cuse 2. Seventeen years ago a 57-year-old man with haematuria was found to have multiple superficial bladder tumours. He was treated with open cystodiathermy and subsequently with intravesical ethoglucid. He relapsed after 4 years with multiple tumours in the bladder and prostatic urethra and underwent total cystourethrectomy.

He was followed up for a further I3 years, remaining free of recurrent disease, until he presented with vague abdominal pain and was found to have a mass in the right ilias fossa 5 x 100 mm and pulmonary metastases which had not been present 3 years earlier. There was no evidence of gynaecomastia and the testes were normal. Apart from some anaemia, the other abnormal investi- gation was a serum fl-HCG of 161 u/l.

C T scan confirmed the previous findings and revealed no other abnormality apart from the mass in the RIF and involved external iliac nodes. Needle biopsy showed a very poorly differentiated carcinoma replacing lymph nodes. There was marked pleomorphism with bizarre giant multinucleate cells. The cytoplasm was eosinophilic

1 1 1 1 1 1 1 1 1 1 1 1 ' 7

0 4 8 I2 16 20 24 28 17 3b 40 44 68 5;

Fig. 1 Cuse 1. Patient with intra-abdominal metastatic bladder carcinoma. Response to combination chemotherapy is shown by a fall in all tumour markers to normal levels. EP = etoposide and cisplatin. OMB = vincristine, methotrexate and bleomycin

TREATMENT OF BLADDER CARCINOMA USING A GERM CELL CHEMOTHERAPY PROTOCOL 475

in most areas and one area showed a more trabeculated pattern with clear or vacuolated cytoplasm. The appear- ances were compatible with recurrence of a transitional cell carcinoma.

In view of the finding of metastatic transitional cell carcinoma with elevated germ cell marker, treatment was started with full dose etoposide and cisplatin alternating with OMB. Courses were alternated at 10- day intervals but the doses of cisplatin and methotrexate were reduced because of mild renal impairment (serum creatinine 250 pmol/l). After 4 weeks an improvement was seen in the chest X-ray, although the abdominal mass remained palpable. At 7 weeks the /I-HCG level had returned to normal and remained so (Fig. 2).

A total of 8 courses of chemotherapy were given over 1 I weeks and following this a C T scan of the abdomen showed the soft tissue mass to be much smaller with a maximum diameter of 5 cm. Associated thickening of the anterior abdominal wall had diminished.

The patient remained well, apart from a resolving peripheral neuropathy 4 months after treatment, but later died.

Case 3. A 54-year-old man presented with a T4 transi- tional cell carcinoma of the bladder, invading the rectum. He was irradiated to 6600 cCy. Cystoscopy 7 months later showed oedematous areas at the bladder base, although biopsy showed no evidence of recurrent tumour. Bimanual examination showed diffuse thickening of the pelvic tissues consistent with post-radiotherapy changes. He subsequently developed rectal pain, tenesmus and partial left ureteric obstruction. C T scan showed no obvious pelvic or abdominal extension of the tumour,

Cisplat in 90 mq V,Tx 300mg

Fig. 2 Case 2. Patient with an abdominal mass and pulmonary metastases, 9 years after total cystectomy, and elevated serum /I- HCG levels. Response to Chemotherapy. ET = etoposide. CSP = cisplatin. OMB = vincristine, methotrexate and bleomycin

although there was infiltration of the tissues between the rectum and bladder. Sigmoidoscopy showed rectal in- volvement and a biopsy confirmed a poorly differentiated transitional cell carcinoma. This was inoperable and a palliative colostomy was carried out. There was no evidence of disseminated disease but /I-HCG was elevated to I22 $1.

Combination chemotherapy was started, using reduced doses of cisplatin and methotrexate in view of some renal impairment. Treatment was started on a similar chemo- therapy protocol as the earlier patients. This resulted in a general improvement in well-being with a reduction in analgesic requirements and a rapid fall in the tumour marker levels (Fig. 3). There was a 6-week interval in the treatment regime when his /I-HCG rose steeply, falling again after reinstatement of chemotherapy.

Discussion

The basic biology of human chorionic gonadotro- phin and its p subunit is well known. High levels of p-HCG have been found in the sera of patients with tumours of the breast, lung, stomach and testis, in addition to the more frequently described placental and extragonadal choriocarcinoma.

Javadpour (1979) analysed 400 patients with active non-seminomatous germ cell tumours of the testis and found 60% to have elevated serum HCG levels, and 7% of patients with testicular seminomas to have raised levels.

It is now established that secretion of one or

Fig. 3 Case 3. Patient with advanced pelvic recurrence of carcinoma of the bladder following radiotherapy and elevated serum P-HCG levels. The initial response was followed by a relapse which responded promptly to a further course of chemotherapy. ET = etoposide. CPjCSP = cisplatin. OMB = vincristine, methotrexate and bleomycin.

476 BRITISH JOURNAL OF UROLOGY

more tumour markers, P-HCG, AFP, placental alkaline phosphatase (PLAP) and lactate dehydro- genase (LDH), occurs in the majority of anaplastic germ cell tumours, and high initial serum concen- trations carry adverse prognostic implications. Response to treatment by gonadotrophin-secreting tumours may be measured by a fall in the levels of B-HCG and other markers, and recurrent disease is invariably found if the levels rise subsequently. Although the transitional epithelium of the bladder may show many types of metaplasia, endocrine manifestations are rarely seen, possibly because they are not routinely assayed. Bladder tumours associated with ectopic gonadotrophin production may be either true choriocarcinomas arising in the bladder, or transitional cell carcinomas with the capacity to secrete gonadotrophin. Shah et al. (1986) reported that only 11 cases of choriocarci- noma of the bladder had been recorded in the literature since 1904 and only 2 of them were associated with transitional cell carcinoma alone- the remainder being choriocarcinomas alone, ele- ments of choriocarcinoma with transitional cell carcinoma or undifferentiated carcinomas.

Retrospective analysis of 104 cases of transitional cell carcinoma of the bladder by Shah et al. (1 986), using an indirect immunoperoxidase method for p- HCG, showed 12 to be positive for P-HCG production. In one such biopsy occasional multi- nucleate giant cells were present and these stained intensely for /I-HCG. It is significant that in this case, the serum p-HCG was raised to 25,000 iu/l and after partial cystectomy the level dropped to 3 iu/l. Recorded cases of transitional cell carcinoma associated with /I-HCG secretion are rare. The first documented case was of a 74-year-old man who underwent partial cystectomy for a poorly differ- entiated transitional cell carcinoma, stage T1. The presence of syncytial giant cells in the tumour prompted a search for gonadotrophin production and a titre of 10,000 iu in a 24-h urine specimen was found. This decreased to undetectable levels by the ninth post-operative day.

Five months after operation the patient remained free of recurrence of tumour (Civantos and Rywlin, 1972). Rodenburg et af. (1985) reported a further case of poorly differentiated transitional cell bladder carcinoma with bony metastases. No gynaecomas- tia was evident, but the serum P-HCG was raised at 46 iu/l. No giant cells were seen in the biopsy. In this case chemotherapy according to a germ cell tumour protocol was given; it consisted of cisplatin, vinblastine and bleomycin, but after one course bone pain increased and the P-HCG increased to

90iu/l with a fatal outcome despite a modified

The 3 patients in this study represent an attempt to apply a rational scheme of chemotherapy based on the finding of elevated serum germ cell tumour markers. Each presented with advanced disease, either locally invasive or metastatic, and the finding of elevated serum markers suggested the adoption of chemotherapy specifically directed against germ cell tumours.

Newlands et al. (1986) used combination chem- otherapy in patients with anaplastic germ cell tumours, achieving an overall survival rate of 89%. Of 149 patients with metastatic disease, 134 had a testicular primary, but there were other sites of primary disease : retroperitoneum (7), mediastinum (9, unknown primary site (3).

The response rate was obtained using treatment with POMB/ACE (platinum, vincristine (oncovin), methotrexate, bleomycin, actinomycin D, cyclo- phosphamide and etoposide). Poor prognostic factors included large tumour bulk and serum concentrations of HCG > 50,000 iu/l and AFP > 500 ku/l. In none of our 3 patients did the serum concentration of P-HCG approach such high levels. Treatment was initiated using a combination of etoposide and cisplatin (EP) and was followed by alternating courses of vincristine, methotrexate and bleomycin (OMB) at 10-day intervals.

Response to treatment was defined as the disappearance of clinical and biochemical evidence of disease. It is of interest that the patient with the highest levels of /I-HCG and AFP had a durable complete response, whereas the 2 with more modest production had a partial response.

In case 1 the elevated serum markers returned to normal by 10 weeks, following 2 courses of EP and OMB; these normal levels were accompanied by objective improvement in the clinical evidence of disease. No recurrent disease had occurred.

In case 2, a lower initial level of serum P-HCG was seen to fall with initiation of combination chemotherapy and again objective evidence of tumour resolution was found with CT scans, showing a reduction in volume of the abdominal mass and resolution of pulmonary metastases.

Case 3 illustrates the effect of chemotherapy on locally invasive disease, in terms of reduction of pain intensity and analgesic requirement, again accompanied by a fall in elevated tumour marker levels, and the necessity of continuing surveillance to detect relapse (Fig. 3).

It appears that P-HCG production tends to occur in less differentiated tumours, being associated with

protocol.

TREATMENT OF BLADDER CARCINOMA USING A GERM CELL CHEMOTHERAPY PROTOCOL 477

fetal gene expression during oncogenesis associated with the production of other substances such as alphafetoprotein and carcinoembryonic antigen. It may be that production of these markers by transitional cell carcinoma is more common than previously recognised. Since they provide a conve- nient and easily detectable index of tumour re- sponse, as well as an indication that the tumour may be sensitive to an appropriate chemotherapeu- tic regime directed against anaplastic germ cell elements, then a search for such markers in serum and urine may be of help in planning appropriate treatment.

References Civantos, F. and Rywlin, A. M. (1972). Carcinomas with

trophoblastic differentiation and secretion of chorionic gona- dotrophins. Cancer, 29,789-798.

Dailey, J. E. and Marcuse, P. M. (1969). Gonadotrophin- secreting giant cell tumor of the lung. Cancer. 24.388-396.

Javadpour, N. (1979). Serum and cellular biologic tumor markers in patients with urologic cancer. Hum. Parhol., 10, 557-568.

Kawamura, J., Machida, S., Yoshida, 0. et al. (1978). Bladder

carcinoma associated with ectopic production of gonadotro- phin. Cancer, 42,2773-2780.

McKechnie, J. C. and Fechner, R. E. (1971). Choriocarcinoma and adenocarcinoma of the esophagus with gonadotrophin secretion. Cancer, 27,694-702.

Newlands, E. S., Bagshawe, D. D., Crawford, S. M. et al. (1986). Current optimum management of anaplastic germ cell tumours of the testis and other sites. Br. J . Urol., 58, 307-3 14.

Regan, J. F. and Cremin, J. H. (1960). Chorionepithelioma of the stomach. Am. J . Surg., 101,224-233.

Rodenburg, C. J. gnd Nieuwenhuyzen Kruseman, A. C. (1985). Immunohistochemical localisation and chromatographic characterisation of human chorionic gonadotrophin in a bladder carcinoma. Arch. Parhol. Lah. Med. , 109, 1046-1048.

Shah, V. M., Newman, K., Crocker, J. et al. (1986). Ectopic beta human chorionic gonadotrophin production by bladder urothelial neoplasia. Arch. Pothol. Lah. Med. , 110, 107-1 11.

The Authors Grant Williams, MS, MSc, FRCS, Consultant Surgeon, Nephro-

R. A. Colbeck, FRCS, Hon. Senior Registrar in Urology,

S . M. Crawford, MD, FRCP, Director, Clinical Oncology,

urology Unit, Harley Street Clinic, London.

Northwick Park Hospital, Harrow.

University of Bradford.

Requests for reprints to: Grant Williams, Flat 3, 43 Wimpole Street, London W I M 7AB.