MVAC-therapy for advanced urothelial carcinoma in an anuric renal transplant recipient

Fritz K. Matzkies1, Bernd Tombach2, Markus Dietrich1, Klaus Kisters1, Michael Barenbrock1, Roland M. Schaefer1, Wolfgang E. Berdel3 and Karl H. Rahn1

1 Medizinische Poliklinik, 2 Radiologische Abteilung and 3 Medizinische Klinik A: Hämatologie- Onkologie, Westfälische Wilhemsuniversität Münster, Germany

Correspondence and offprint requests to: Dr Fritz Matzkies, Westfälische Wilhelms- Universität Münster, Medizinische Poliklinik, Albert-Schweitzer- Str. 33, D-48129 Münster, Germany. E-mail: matzkies{at}uni-muenster.de.

Keywords: chemotherapy; haemodialysis; MVAC; renal transplant; urothelial carcinoma



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
Chemotherapy due to malignancy in patients with reduced kidney function is not without the risk of serious complications. There are no randomized, controlled studies with large patient numbers to prove the possible use of chemotherapy in patients with chronic renal insufficiency. Besides the increased risk of toxicity due to reduced renal excretion rate there are also no dosage guidelines for the different chemotherapy regimens. With respect to chronic haemodialysis patients only a few case reports exist providing small information about dosages and outcome. This deficiency in information faces a growing number of patients after transplantation with often long lasting immunosuppression and therefore increased risk of malignancy.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
We report on a 35-year-old patient with renal insufficiency due to chronic glomerulonephritis. Haemodialysis was started in February 1992. Renal transplantation was performed in November 1992. In 1994 the patient showed persistent haematuria and urothelial carcinoma was diagnosed. Diagnostic procedures showed an extensive involvement of both kidneys and the urothelium of the bladder together with abdominal and pelvic lymphadenopathies. Curative surgery (Ro) with removal of the spleen, the two kidneys, the prostate, the bladder and numerous lymph nodes was performed. Since renal transplant function was stable the transplanted kidney was not removed and a uretero-intestinal anastomosis to a neo-bladder of the small intestine was performed.

After this operation there was a long time period with reduced, although sufficient, renal function. The patient had intermittent micro-haematuria, due to various bacterial infections of the neo-bladder. Repeated urological control examinations gave no hint of recurrence of urothelial carcinoma.

In December 1997, the patient presented with macro-haematuria and acute rejection of the renal transplant. Shortly before admission conversion from cyclosporin to FK 506 was performed and urinary tract infection was present. Despite antibiotic therapy the macro-haematuria persisted. An ultrasound of the renal transplant showed a tumour located in the central echogenic complex. Computerized tomography of the kidney showed a solid structure in the renal pelvic system (Figure 1Go). Cystoureteroscopy confirmed the suspicion of a relapse of urothelial cancer (Figure 2Go). In addition to the infiltration of the transplanted kidney computerized tomography showed advanced abdominal and pelvic lymphadenopathies, without evidence of metastatic disease of liver or lungs. Operation in January 1998 with removal of the kidney graft and abdominal and pelvic lymphadenectomy confirmed the diagnosis of advanced disease (T3, N1, Mo, G3, Ro). Pathological examination revealed haematogenic infiltration of the kidney cortex. Since the patient was young and in good physical shape adjuvant polychemotherapy according to the MVAC (methotrexate, vinblastine, adriablastine and cisplatin) protocol was discussed. Despite the high risk of side effects and the questionable usefulness of chemotherapy these issues were intensely discussed with the patient who nonetheless opted for treatment. Since the patient was anuric, chemotherapy was given in reduced dosages: methotrexate (MTX) 15 mg/m2, cisplatin 30 mg/m2, vinblastine 1.5 mg/m2, doxorubicine 15 mg/m2. First MTX dosage was given in the evening after regular haemodialysis procedure at day 1 of the chemotherapy protocol. At day 2 leucovorine rescue therapy with intravenous dosage of 15 mg/m2 was started. Haemodialysis with a high-flux polysulfone membrane (F 60, Fresenius, Bad Homburg) was performed before the remaining chemotherapy with vinblastine, doxorubicine and cisplatine was given at day 2. In the following days continuous daily haemodialysis and leucovorine rescue therapy were done until MTX values, determined before haemodialysis, fell below 0.01 µmol/l (detection limit). From day 3 to day 7 dexametasone therapy with three times 4 mg/day was given. At day 15 and day 22 of chemotherapy additional MTX and vinblastine dosages were given in the above mentioned dosages with the same precautions after MTX application as before. The exact data for MTX levels after the four cycles are given in Table 1Go.



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Fig. 1. Computerized tomography of the renal transplant kidney showing contrast medium enhancement of the suspect structure in the renal pelvic system.

 


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Fig. 2. Pyelography of the renal transplant with typical findings.

 

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Table 1. Methotrexate (MTX) levels after each MVAC chemotherapy cycle
 
Since MTX dosage was very low no folic acid rescue therapy was given after the application of the first cycle of chemotherapy. At day 7 the patient developed painful oral mucositis (WHO grade III) and scrotal candidiasis together with leukocytopenia. Under combined antibiotic and antifungal therapy the patient recovered fast and chemotherapy was continued. The following second cycle of MVAC therapy was performed with reduced dosages of cisplatin 15 mg/m2 and MTX 7.5 mg/m2 and additional folic acid rescue therapy beginning after haemodialysis, at day 2. In the last three cycles of MVAC therapy cisplatin and MTX dosages were given again according to the first protocol with 15 mg/m2 and 30 mg/m2 and additional folic acid rescue therapy. The last three cycles of the MVAC therapy were well tolerated, without new episodes of leukocytopenia and candidiasis. As a major side effect thrombosis of the Cimino fistula occurred after the third cycle of chemotherapy. After successful revascularization further haemodialysis sessions were performed via a single lumen Shaldon catheter. Chemotherapy was performed between March and July 1998. Thereafter the patient recovered fast and underwent continuous haemodialysis treatment in an outpatient facility.

He was readmitted in September 1998 with dry cough, night sweat and sonomorphologic suspicion of liver metastases. Computerized tomography confirmed the presence of multiple metastases of all liver sections, abdominal lymphadenopathy and multiple metastases in both lungs. The patient died from terminal cancer in October 1998.



   Discussion
 Top
 Introduction
 Case
 Discussion
 References
 
Despite nearly complete extirpation of the urinary tract our patient showed recurrent urothelial cancer in the renal transplant after 3 years. Intermittent micro-haematuria was masked by persisting urinary tract infections due to immunosuppression and the neo-bladder of small intestine. Since local invasive growth of the urothelial cancer into the pelvic system of the renal transplant must be assumed, extirpation of the transplanted kidney might have been curative at that time and should be discussed in comparable cases.

MVAC chemotherapy is an established therapy in advanced urothelial carcinoma with tolerable toxicity and a complete response rate of 36%, with a high relapse rate (66%) and a median survival time of 9 months [1]. In addition adjuvant MVAC therapy after radical cystectomy proved to be efficious in prolonging relapse free survival [24]. Preoperative staging investigations revealed an extensive disease progress in our patient. Therefore neoadjuvant MVAC therapy could have been discussed [5]. However, histological confirmation was only possible by nephrectomy since cytological investigations were negative. Therefore the patient opted for primary operation.

According to our literature search there is only one case report by Yokogi et al. on MVAC therapy in an anuric dialysis patient with urothelial cancer, describing tolerable toxicity [6]. Since the use of high-flux haemodialysis membranes has been recommended for MTX removal [7] we performed chemotherapy in reduced dosages and found comparable results for MTX removal with a fast reduction of high MTX serum levels during the first haemodialysis session and long lasting, relatively low MTX levels in the following days after application.

Based on our findings we confirm a tolerable toxicity of MVAC chemotherapy according to the reduced dosage schedule used in our haemodialysis patient. Repeated MTX measurements and daily haemodialysis sessions with a high-flux membrane as well as leucovorin rescue therapy are required to avoid the toxicity of even very low MTX doses. Survival time was comparable to the above mentioned studies in non-anuric patients. Since we did not induce leukocytopenia in the last three chemotherapy cycles even higher doses of MTX and cisplatin should be discussed since the efficiency of daily haemodialysis with high-flux membranes is relatively high.

In conclusion, although obviously only of limited long term efficacy in the patient presented here, MVAC chemotherapy with dose reduction is feasible in anuric haemodialysis patients.



   References
 Top
 Introduction
 Case
 Discussion
 References
 

  1. Witjes JA, Wullink M, Oosterhof GO, de Mulder P. Toxicity and results of MVAC chemotherapy in advanced urothelial carcinoma. Eur Urol 1997; 31: 414–419[ISI][Medline]
  2. Stöckle M, Wellek S, Meyenburg W et al. Radical cystectomy with or without adjuvant polychemotherapy for non-organ-confined transitional cell carcinoma of the urinary bladder: Prognostic impact of lymph node involvement. Urology 1996; 48: 868–875[ISI][Medline]
  3. Skinner DG, Daniels JR, Russell CA et al. The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991; 145: 459–467[ISI][Medline]
  4. McCaffrey JA, Hilton S, Mazumdar M et al. Phase II randomized trial of gallium nitrate plus fluorouracil versus methotrexate, vinblastine, doxorubicin, and cisplatin in patients with advanced transitional-cell carcinoma. J Clin Oncol 1997; 15: 2449–2455[Abstract]
  5. Sagaster P, Flamm J, Flamm M et al. Neoadjuvant chemotherapy (MVAC) in locally invasive bladder cancer. Eur J Cancer 1996; 32: 1320–1324
  6. Yokogi H, Yamasaki Y, Ishibe T. M-VAC therapy in a patient with ureteral carcinoma accompanied by chronic renal failure. Gan To Kagaku Ryoho 1993; 20: 2405–2407[Medline]
  7. Wall SM, Johansen MJ, Molony DA, DuBose TD Jr, Jaffe N, Madden T. Effective clearance of methotrexate using high- flux hemodialysis membranes. Am J Kidney Dis 1996; 28: 846–854[ISI][Medline]
Received for publication: 12. 7.99
Accepted in revised form: 8. 9.99





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