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New Preoperative Chemotherapy for Bladder Cancer Using Combination Hemodialysis and Direct Hemoperfusion: Preliminary Report
0022-534 7/84/1311-0036$02.00/0
Vol. 131, January Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1984 by The Williams & Wilkins Co.
NEW PREOPERATIVE CHEMOTHERAPY FOR BLADDER CANCER USING COMBINATION HEMODIALYSIS AND DIRECT HEMOPERFUSION: PRELIMINARY REPORT SADAO KAMIDONO, AKIO FUJII, GAKU HAMAMI, YASUHARU NAKANO, KEIICHI UMEZU, YOSHINORI ODA AND JOJI ISHIGAMI From the Department of Urology, Kobe University School of Medicine, Kobe, Japan
ABSTRACT
Preoperative chemotherapy and subsequent cystectomy were performed on 11 patients with locally invasive bladder cancer. Three chemotherapy regimens were tested: 1) 2 to 3 mg. per kg. doxorubicin in 5 patients, 2) 1 mg. per kg. mitomycin C in 3 and 3) 0.6 mg. per kg. mitomycin C with 70 mg. systemic bleomycin in 3. Doxorubicin and mitomycin C were infused once preoperatively into the hypogastric arteries or the aortic bifurcation, with simultaneous hemodialysis and direct hemoperfusion to remove as much extra-regional infusate as possible and, thus, reduce the systemic toxicity of the drug. Objective responses were obtained in 4 of 7 patients with measurable tumor (57 per cent). Downstaging was obtained in 7 of 11 patients (64 per cent). All patients given doxorubicin had leukocytopenia (500 to 1,900 per mm. 3 ) and moderate patchy alopecia, and 1 patient given mitomycin C and bleomycin had thrombocytopenia (44,000 per mm. 3 ). However, these side effects were observed comparatively less in the patients given mitomycin Conly. As long as the treatment of invasive bladder cancer is limited to surgery no further improvement can be expected. Therefore, a new treatment approach is necessary. Others have reported that preoperative radiation combined with subsequent cystectomy is useful for invasive bladder cancer. 1- 3 We also considered combined modality therapy together with preoperative chemotherapy. Since the results of ordinary single agent chemotherapy have been unfavorable, 4 we developed a new approach by using intra-arterial infusion of anticancer drugs in heavy doses to increase regional drug concentrations and to enhance the antitumor effects. The problem associated with such a trial is the side effects of the drug, that is increased incidence of systemic toxicity owing to elevated concentrations in the extraregional infusate. Since it is important to reduce the systemic toxicity by lowering the levels of extra-regional infusate we used hemodialysis and direct hemoperfusion for this purpose. As we have reported previously, mitomycin C is removed by hemodialysis and direct hemoperfusion. 5 We herein report the results of experimental studies on the removal of doxorubicin by artificial organs (hemodialysis and direct hemoperfusion) and our preliminary experience with intra-arterial infusion of anticancer drugs in heavy doses, concomitantly with hemodialysis and direct hemoperfusion, against invasive bladder cancer.
groups consisted of 4 animals. Hemodialysis and direct hemoperfusion were not used in groups 1 and 2. Continuous intraarterial infusion of doxorubicin was done with an infusion pump during 90 minutes via the hypogastric artery at a drug dose of 1 mg./kg. for group 1 and 4 mg./kg. for group 2. To measure the serum doxorubicin concentration, blood samples were obtained from the subclavian vein 30, 60, 90, 120, 150 and 180 minutes after the beginning of infusion. For group 3, in addition to the aforementioned protocol, hemodialysis and direct hemoperfusion systems, connected in that order, were used concomitantly for 3 hours from the beginning of the infusion. Vascular access was provided by the femoral artery and vein, and blood samples were obtained from 3 different sites, that is the subclavian vein, and pre-artificial and post-artificial organs (dialyzer and column). Clearance of doxorubicin by hemodialysis and direct hemoperfusion was measured from the blood concentrations of doxorubicin (from the dialyzer and column) using the formula of Wolf and associates. 6 Immediately after the blood sampling at 90 minutes 2 of the 4 animals were sacrificed to measure tissue concentrations of doxorubicin in the bladder and prostate. Serum and tissue concentrations were measured by a fluorescence assay.7 Clinical study. We studied 11 patients with histologically proved bladder tumor, including 7 with measurable tumor. All patients were hospitalized between January 1979 and August 1982, and had not received any radiotherapy or chemotherapy before the study. The determination of the clinical stage of bladder cancer was made by excretory urography, bimanual examination of the pelvis with the patient under general anesthesia, computerized tomography (CT), lymphangiography and chest radiography. Bone and liver radionuclide scans were done when indicated clinically. Because of the need to evaluate this new therapy, transurethral resection of the tumor was not performed. The response criteria for evaluable disease were defined as 1) complete-complete regression of all measurable bladder tumor, 2) partial->50 per cent decrease in tumor size, 3) minor remission-25 to 50 per cent decrease in tumor size, 4) stable-<25 per cent decrease or increase in tumor size and 5) progression->25 per cent increase in tumor size. Mappings of all resected bladders were made according to the method of
MATERIALS AND METHODS
Experimental study. Doxorubicin (molecular weight 579.98) is a cytotoxic anticancer antibiotic that has a strong tissue affinity and is concentration-dependent. Mongrel dogs (body weight 10 to 15 kg.) were used in the experiments, which were performed under general anesthesia. The experimental design was the same as that used in the previously reported fundamental study on mitomycin C, while the dialysate supply system, dialyzer used for hemodialysis and petroleum charcoal column used for direct hemoperfusion also were of the same specifications.5 Each of the 3 experimental Accepted for publication July 1, 1983. Read at annual meeting of American Urological Association, Las Vegas, Nevada, April 17-21, 1983. Supported in part by grants-in-aid for Cancer Research from Ministry of Education, Science and Culture (57015067), Japan. 36
SHEI\l OT'}1ERAP~"i
Koss a.nd asso,('.iates. 8 of the acute ative vvas associates. 9 A summary of the patients is shown in table 1. Seven tumors were graded as T2 and 4 as T3. Patients 1, 5, 8 and 9 had recurrent tumor. All patients underwent regional chemotherapy 1 intra-arterial infusion with concomitant artificial organs (2 times for patient followed by radical cystectomy with excision of the regional lymph nodes and ilea! conduit urinary diversion 3 to 6 weeks later, except for patients 1 to 3 and 8 who underwent staged ilea! conduit urinary diversion before chemotherapy. Three chemotherapy regimens were tested: 1) 2 to 3 mg./kg. doxorubicin, 2) l mg./kg. mitomycin C, and 3) 10 mg. bleomycin daily on days 1 to 7 and 0.6 mg./kg. mitorn.ycin C on day 8. Doxorubicin and mitorn.ycin C were infused into both hypogastric arteries or the aortic bifurcation by Seldinger's method, while bleomycin was given by systemic infusion. Doxorubicin and mitomycin C were given continuously for 90 minutes using infusion pumps, and the artificial organs were used at the same time for 3 hours. Vascular access for the arterial line during hemodialysis and direct hemoperfusion was provided, either in the radial artery or inferior vena cava, and the blood was returned to the antecubital vein after it had passed through the artificial organs (fig. For direct hemoperfusion a petroleum charcoal column identical to that in the animal experiment was used. For hemodialysis the dialysate system was TM 101 (a sorbent-based recirculating dialysate regeneration system) with a hollow fiber dialyzer (C-DAK 1.3 artificial kidney, model 4), with a creatinine clearance at 200 ml. per minute and blood flow of 133 ml. per minute. To determine the rate of removal the artificial organs the serum concentrations of the drugs were measured at 30, 60, 90, 120, 150 and 180 minutes, and the total urinary concentration was measured for 3 hours from the beginning of treatment. Objective responses were evaluated 3 weeks after regional chemotherapy. RESULTS
In the experimental study the serum anticancer drug concentrations showed that the serum doxorubicin level in group 3 animals with the concomitant use of the artificial organs was the lowest, doxorubicin clearance of the artificial organs was higher when the serum drug level was high and the mean rate TABLE 1.
Pt. No.-Age-Sex
Clinical Stage
1-70-M
T3
I1
2-67-M
Tumor Grade*
Drug ( mg. per dose)
of clearance was 79.5 ml pei' minute 2). Tissue levels of doxorubicin in the bladder and prostate not decrease even when the artificial organs were used concomitantly (table 2). Serum concentrations of doxorubicin and mitomycin C in the clinical study were similar to those obtained in the animal experiments (figs. 3 and 4). The clearance to the time of completion of the drug infusion averaged 95. 7 ml. per minute for doxorubicin and 116. 7 ml. per minute for mitomycin C. Thus, mitomycin C was cleared at a higher rate. The removal rate varied greatly from 7.0 to 35.9 per cent of the administered dose of doxorubicin and 8.5 to 23.9 per cent of mitomycin C (table 3). The rate of removal of doxorubicin in patient 4 was 35.9 per cent of the administered dose, which was much higher than in the others. Hemodialysis was not used and 2 units of the column served as the artificial organs. The total urinary recovery rates up to 3 hours after administration were 2.8 to 9.0 per cent and 0.1 to 4.8 per cent of the administered doses of doxorubicin and mitomycin C, respectively (table 3). Objective responses (partial or complete) were obtained in 3 of 4 patients given doxorubicin and 1 of 3 given mitomycin C. The CT scan of patient 3 showed a large pelvic mass before therapy (fig. 5, A) but marked regression after therapy (fig. 5, B). Turn.or downstaging was seen in 4 of 5 patients treated with doxorubicin, 2 of 3 given mitomycin C, and 1 of 3 treated with bleomycin and mitomycin C. These 7 patients are alive with no evidence of recurrent tumor. Systemic toxicity was evaluated by a 5 grade system (0 through 4). Moderate and patchy alopecia (grade 2) as well as moderate to severe leukocytopenia (grades 2 to 4) was observed in all patients treated with doxorubicin, and thrombocytopenia was seen in only l patient. No cardiac, hepatic or renal toxicity was found in any of these patients and none complained of nausea or vomiting. Toxicity observed in the mitomycin C group was moderate (grades 1 and 2). Thrombocytopenia (grades 2 and 3) was noted in 2 patients treated with bleomycin and mitomycin C. In 1 patient treated with doxorubicin severe motor disturbances of the lower extremities were seen. Unexpected local toxicity was observed even by the concomitant use of this therapy, since 8 patients suffered mild localized pain that was considered to be the result of treatment. However, such severe reactions as necrosis or ulceration of the buttocks were not seen. A transient decrease of thrombocytes owing to adsorption of thrombocytes to direct hemoperfusion was seen in all patients but the degree was light and there were no clinical problems.
Clinical summary Artery Infused
Artificial Organs (ml./min.)
T3
III
Doxorubicin (100) Doxorubicin (150) Doxorubicin (150)
3-63-M
T2
III
Doxornbicin ( 150)
Bifurcation of aorta
4-65-M
T2
II
Doxorubicin (120)
Bifurcation of aorta
5-36-M
T3
II
Doxorubicin (150)
Bifurcation of aorta
6-69-M
T3
Squamous
Mitomycin C (60)
Rt. hypogastric
7-65-M
T2
III
Mitomycin C (50)
Bifurcation of aorta
8-74-M
T2
II
Mitomycin C (50)
Bifurcation of aorta
Hollow fiber kidney, column (150) Hollow fiber kidney, column (200) 2 units of column (150)t
9-52-M
T2
II
2 units of column (150)t
T2
III
Bilat. hypogastric
2 units of column (150)t
11-68-M
T2
II
Mitomycin C (42), bleomycin (70) Mitomycin C (34), bleomycin (70) Mitomycin C (38), bleomycin (70)
Bifurcation of aorta
10-73-M
Bilat. hypogastric
2 units of column (150)t
Patients 1 to 4 and 6 to 8 had measurable tumor.
* World Health Organization. t Hemosorba or DHP-1 column.
37
BLADilEi~, C1-\),JCER CONCOlV1Ir;AI\lT Vi!'TJ-I ARTIFICIAL ORGAI'
Bilat. hypogastric Bilat. hypogastric
Hollow fiber kidney, column (150) Hollow fiber kidney, column (150) Hollow fiber kidney, column (150) Hollow fiber kidney, column (150)t 2 units of column (150)t
Vascular Access (arterial line-venous line) Radial artery-antecubital vein Radial artery-antecubital vein Radial artery-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Radial artery-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein
38
KAMIDONO AND ASSOCIATES TABLE 2.
Concentration of doxorubicin in bladder and prostate by group Bladder (mcg./gm.)
Group 1-1 mg./kg. doxorubicin* Group 2-4 mg./kg. doxorubicin* Group 3-4 mg./kg. doxorubicint
Trigone
Dome
Prostate (mcg./gm.)
9.9 54.5 58.7
4.1 38.6 31.8
9.1 80.7 75.0
* Intra-arterial infusion. t Intra-arterial infusion, hemodialysis and direct hemoperfusion.
A
~
~ a.
'QO
solid line : pre- artificial organs dotted line ; post-artificial organs 1 4 : patient : patient 2 0 ; patient 3
Intra-arterial infusion of P.DM
E
5. 0
•
0
E
arterial infusion of ADM or MMC ( to hypogastric artery or bifurcation of aorta)
:i:
: patient ; patient
0
<(
FIG. 1. Clinical design of regional chemotherapy given by intraarterial infusion with concomitant artificial organs. HD, hemodialysis. DHP, direct hemoperfusion. RA, radial artery. IVC, inferior vena cava. ADM, doxorubicin. MMC, mitomycin C.
.... 0
4 5
1.0
C:
..., ...,~ 0.5
.Q
C: Q)
0
C:
[}--{] Group 1 ( ADM 1 mg per kg) non-artificial organs <>--0 Group 2 ( ADM 4 mg per kg) non-artificial organs •·-eGroup 3 (ADM 4 mg per kg) artificial organs Intra- arterial infusion of ADM 1--=.=...:=.:..:.=.c.cc_c.c..:.:=.c..:::.:...==-.J (HD+DHP)
A
~ E
~
a.
5. 0
0
0
E
...
::, Q)
(/)
0. 1 0
8
(each group, n = 4)
'QO
0
E
,....._
:i:
·e ...
C:
0
Clearance of ADM
100
~ ; mean value
Q)
:: 1.0
a.
0
~-- - _..o-----~ - - --iJ,
C:
2 0.5
I
~C:
I
Q)
0
I
0
ti 1/
"" ,5 '
..- -----
//
C:
0
I
Q)
'
C:
-~,,
,
...
50
'
Q)
" '~
I'
E
n=5
0
__.o.._ - - - - - '-,
u
'
2
Q)
(/)
Clearance of ADM ®--0 : mean value ~ : range
8
100 C:
·e
,._
0
30
60
90
120
150
180
Time (min)
FIG. 3. A, serum concentration of doxorubicin (ADM) in blood samples of pre-artificial and post-artificial organs by patients. B, clearance of doxorubicin by artificial organs in 5 patients. Blood flow rate is 150 ml. per minute.
Q)
a.
"" ,5
50
n=4
Q)
0 C:
Q)
0
0
30
60
90
120
150
180
Time (min)
FIG. 2. A, serum concentration of doxorubicin (ADM) in subclavian vein by group in mongrel dogs. HD, hemodialysis. DHP, direct hemoperfusion. B, clearance of doxorubicin by artificial organs in group 3. Blood flow rate is 140 ml. per minute. DISCUSSION
The incidence of side effects caused by regional chemotherapy given by intra-arterial infusion is said to be lower generally compared to systemic administration. However, some anticancer drugs induce systemic toxicity equivalent to that seen during systemic administration .10• 11 Doxorubicin is one such antican-
cer drug. According to Chen and Gross, since doxorubicin is eliminated by biliary excretion and liver metabolism there would be no decrease in systemic toxicity but merely an increase in the regional drug concentration when it is infused in an organ other than the liver. 11 Since mitomycin C primarily is metabolized in the liver a similar mechanism is postulated. 12 From these points, the usefulness of concomitant hemodialysis and direct hemoperfusion during the intra-arterial infusion of anticancer drugs in heavy doses could be supported for the treatment of bladder cancer. Since experiments showed that the extra-regional serum drug concentrations were low because doxorubicin and mitomycin C were removed by the artificial organs, a decrease in systemic toxicity was expected. Objective responses were obtained in 75 per cent of the patients treated with doxorubicin and 33 per cent of those treated with mitomycin C. Of course, the trial number was small and comparison with other studies is difficult. However, our results are considered to be excellent compared to other reports. 13- 15 Although downstaging was observed in 7 of 11
CHEMOTHERAPY OF BLADDER CANCER CONCOMITANT WITH ARTIFICIAL ORGANS
...
solid line : pre-artificial organs dotted line : post-artificial organs
8. Ill)
0.5
1 0 :::!E :::!E
0
• •
: patient : patient
6 7
•
: patient
8
0. 1
C
:8
39
patients (64 per cent) there was a small discrepancy between the downstaging and objective responses . The purpose of chemotherapy in our procedure is not to sterilize the primary tumor but to reduce systemic toxicity to permit an early radical operation following chemotherapy. The mean preoperative interval was 30 days and such a relatively long interval was partly owing to careful evaluation of the systemic toxicity in relation to the appearance of side effects. 12
~ 0.05 5i0 C
0 0
E
2
Jl
150
B
Clearance of MMC mean value
C!)ooo0 ·
100 L Q)
Q.
! Q)
g
50
f
0
0
30
60
90
120
150
180
Time (min)
FIG. 4. A, serum concentration of mitomycin C (MMC) in blood samples of pre-artificial and post-artificial organs by patient. B, clearance of mitomycin C by artificial organs in 3 patients. Blood flow rates are 150 to 200 ml. per minute. TABLE 3.
Results of preoperative chemotherapy Survival (mos.)
Removal Rate of Extra-regional Anticancer Drugs Mg.(%)
Urinary Recovery in ;a,3 Hrs. Mg.(%)
Hair, local pain Leukocytes
48, no evidence of disease
9.2 (9.2) 19.3 (12.9)
13.5 (9.0)
2 3
Hair, local pain Leukocytes
11, dead
14.6 (9.7)
5.5 (3.7)
pT2 (T3)
2 3 4
Hair Local pain Leukocytes
41, no evidence of disease
10.5 (7.0)
7.6 (5.1)
4
pTl (T2)
1 2
Platelets Hair, local pain, leukocytes
18, no evidence of disease
43.1 (35.9)
3.3 (2.8)
6
pTl (T2)
2 3 4
Hair Leukocytes, local pain Neurotoxicity
12, no evidence of disease
36.6 (24.4)
11.3 (7.5)
4
pT4 (T3)
1
Serum glutamic pyruvic transaminase, nausea Serum glutamic oxaloacetic transaminase, local pain
5, dead
5.1 (8.5)
0.7 (1.2)
26, no evidence of disease
6.2 (12.4)
2.4 (4.8)
7, no evidence of disease
2.8 (10.0)
0.6 (2.1)
11, no evidence of disease
3.9 (9.3)
0.9 (2.1)
Objective Response*
Interval to Operation (wks.)
Pathologic Stage (clinical stage)
Grade of Toxicity
1
Partial
4
pTl (T3)
2 3
2
Partial
3
pT3 (T3)
3
Partial
4
4
Minor remission
Pt. No.
5
6
Partial
FIG. 5. Patient 3. CT scans show response to regional chemotherapy of pelvic lesion that was proved at operation. A, before chemotherapy. B, after chemotherapy.
2
Complications
7
Stable
6
pTl (T2)
1
Local pain, platelets
8
Stable
6
pTl (T2)
1
Leukocytes
9
3
pT2 (T2)
10
3
pT2 (T2)
1 3
Leukocytes Platelets
7, dead
6.7 (19.7)
0.4 (0.1)
11
3
pTl (T2)
1 2
Leukocytes, local pain Platelets
6, no evidence of disease
9.1 (23.9)
0.3 (0.1)
None
* Partial response-50 per cent by CT scan in the sum of the products of S::2 perpendicular diameters, minor remission-25 to 49 per cent decrease in tumor size and stable-25 per cent decrease in tumor size.4
40
KAMIDONO AND ASSOCIATES
From the difference in the serum drug concentrations in the animals with and without the use of artificial organs,5 the amount of anticancer drug removed in the clinical study and the clinical results of side effects, our treatment certainly is considered to be useful. However, further extensive studies are required because removal of the anticancer drugs by the artificial organs did not reduce necessarily the incidence of the side effects. We are continuing this method because the amount of drug removed with a column of 2 units in patient 4 was reduced considerably. A shortening of the preoperative interval also may be expected. Despite a higher rate of clearance of mitomycin C by the artificial organs compared to that of doxorubicin, the latter group showed a greater quantity of drug removed. This finding probably was owing to the higher dose of doxorubicin and the higher serum concentrations achieved. The artery used for infusion or the location of the vascular access varied slightly among the patients but this did not result in marked differences in objective responses or systemic and local toxicity. REFERENCES 1. Whitmore, W. F., Jr., Batata, M.A., Ghoneim, M.A., Grabstald, H. and Una!, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. 2. Skinner, D. G.: Current perspectives in the management of highgrade invasive bladder cancer. Cancer, suppl. 7, 45: 1866, 1980. 3. Boileau, M.A., Johnson, D. E., Chan, R. C. and Gonzales, M. 0.: Bladder carcinoma: results with preoperative radiation therapy and radical cystectomy. Urology, 16: 569, 1980. 4. Yagoda, A.: Chemotherapy of metastatic bladder cancer. Cancer, suppl. 7, 45: 1879, 1980. 5. Kamidono, S., Hamami, G., Fujii, A. and Ishigami, J.: A fundamental study of regional chemotherapy given by intraarterial infusion with concomitant hemodialysis and hemoperfusion. Invest. Urol., 19: 176, 1981. 6. Wolf, A. V., Remp, D., Kiley, J. E. and Currie, G. D.: Artificial kidney function: kinetics of hemodialysis. J. Clin. Invest., 30: 1062, 1951. 7. Rosso, R., Ravazzoni, C., Esposito, M., Sala, R. and Santi, L.: Plasma and urinary levels of adriamycin in man. Eur. J. Cancer, 8: 455, 1972. 8. Koss, L. G., Tiamson, E. M. and Robbins, M.A.: Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. J.A.M.A., 227: 281, 1974. 9. Miller, A. B., Hoogstraten, B., Staquet, M. and Winkler, A.: Reporting results of cancer treatment. Cancer, 47: 207, 1981. 10. Haskell, C. M., Eilber, F. R. and Morton, D. L.: Adriamycin (NCS123127) by arterial infusion. Cancer Chemother. Rep., part 3, 6: 187, 1975. 11. Chen, H. S. and Gross, J. F.: Intra-arterial infusion of anticancer drugs: theoretical aspects of drug delivery and review of responses. Cancer Treat. Rep., 64: 31, 1980. 12. Murinson, D. S.: Clinical pharmacology of antineoplastic agents.
In: Practical Cancer Chemotherapy. Edited by S. N. Rosenthal and J.M. Bennett. New York: Medical Examination Publishing Co., Inc., chapt. 2, p. 14, 1981. 13. Pavone-Macaluso, M.: Chemotherapy of vesical and prostatic tumours. Brit. J. Urol., 43: 701, 1971. 14. Middleman, E., Luce, J. and Frei, E., III: Clinical trials with adriamycin. Cancer, 28: 844, 1971. 15. Kraybill, W. G., Harrison, M., Sasaki, T. and Fletcher, W. S.: Regional intra-arterial infusion of adriamycin in the treatment of cancer. Surg., Gynec. & Obst., 144: 355, 1977. EDITORIAL COMMENTS The clinical experience is small but impressive. Cisplatin might have been used after animal experimentation, since most of the agent is taken up by the first capillary bed when given intra-arterially during 48 hours. It is important to have these techniques in place but the real problem is that we do not understand the fundamentals of the primary and/or metastatic growth rates nor do we presently have effective drugs for any adjuvant role. George R. Prout, Jr. Department of Urology Massachusetts General Hospital Boston, Massachusetts The authors have presented an interesting feasibility study. Their data reveal a significant reduction in serum concentration of drug achieved by hemodialysis and direct hemoperfusion. The tissue levels achieved in the bladder and prostate were not compromised using hemodialysis and direct hemoperfusion (table 2 in article). Systemic drug toxicity was not eliminated. Patient 4, in whom a column of 2 units was used, achieved a significant increase in the amount of drug removed. While the data do not allow any statement regarding therapeutic efficacy, their approach is novel and may merit controlled clinical trials. Kenneth B. Cummings Division of Urology Department of Surgery University of Wisconsin Hospital and Clinics Madison, Wisconsin REPLY BY AUTHORS We completed animal experiments with cisplatin, which revealed that about 50 per cent of the total administration dosage was absorbed and removed from the body with direct hemoperfusion. Based on these experimental data a clinical study in which heavy dosage of cisplatin administration is made using direct hemoperfusion is under trial, and it shows fairly good results in the antineoplastic effects against bladder cancer and the reduction of the systemic toxicity of the drug. The administration dosage of either 3.0 mg. doxorubicin or 1.0 mg. mitomycin C per kg. body weight has been considered to be a lethal dosage but all patients were alive for at least 4 months. Thereafter, 3 patients died of cancer and not drug toxicity. Thus, we believe that hemodialysis and direct hemoperfusion must have reduced the systemic toxicity of the agent to some extent.
Vol. 131, January Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1984 by The Williams & Wilkins Co.
NEW PREOPERATIVE CHEMOTHERAPY FOR BLADDER CANCER USING COMBINATION HEMODIALYSIS AND DIRECT HEMOPERFUSION: PRELIMINARY REPORT SADAO KAMIDONO, AKIO FUJII, GAKU HAMAMI, YASUHARU NAKANO, KEIICHI UMEZU, YOSHINORI ODA AND JOJI ISHIGAMI From the Department of Urology, Kobe University School of Medicine, Kobe, Japan
ABSTRACT
Preoperative chemotherapy and subsequent cystectomy were performed on 11 patients with locally invasive bladder cancer. Three chemotherapy regimens were tested: 1) 2 to 3 mg. per kg. doxorubicin in 5 patients, 2) 1 mg. per kg. mitomycin C in 3 and 3) 0.6 mg. per kg. mitomycin C with 70 mg. systemic bleomycin in 3. Doxorubicin and mitomycin C were infused once preoperatively into the hypogastric arteries or the aortic bifurcation, with simultaneous hemodialysis and direct hemoperfusion to remove as much extra-regional infusate as possible and, thus, reduce the systemic toxicity of the drug. Objective responses were obtained in 4 of 7 patients with measurable tumor (57 per cent). Downstaging was obtained in 7 of 11 patients (64 per cent). All patients given doxorubicin had leukocytopenia (500 to 1,900 per mm. 3 ) and moderate patchy alopecia, and 1 patient given mitomycin C and bleomycin had thrombocytopenia (44,000 per mm. 3 ). However, these side effects were observed comparatively less in the patients given mitomycin Conly. As long as the treatment of invasive bladder cancer is limited to surgery no further improvement can be expected. Therefore, a new treatment approach is necessary. Others have reported that preoperative radiation combined with subsequent cystectomy is useful for invasive bladder cancer. 1- 3 We also considered combined modality therapy together with preoperative chemotherapy. Since the results of ordinary single agent chemotherapy have been unfavorable, 4 we developed a new approach by using intra-arterial infusion of anticancer drugs in heavy doses to increase regional drug concentrations and to enhance the antitumor effects. The problem associated with such a trial is the side effects of the drug, that is increased incidence of systemic toxicity owing to elevated concentrations in the extraregional infusate. Since it is important to reduce the systemic toxicity by lowering the levels of extra-regional infusate we used hemodialysis and direct hemoperfusion for this purpose. As we have reported previously, mitomycin C is removed by hemodialysis and direct hemoperfusion. 5 We herein report the results of experimental studies on the removal of doxorubicin by artificial organs (hemodialysis and direct hemoperfusion) and our preliminary experience with intra-arterial infusion of anticancer drugs in heavy doses, concomitantly with hemodialysis and direct hemoperfusion, against invasive bladder cancer.
groups consisted of 4 animals. Hemodialysis and direct hemoperfusion were not used in groups 1 and 2. Continuous intraarterial infusion of doxorubicin was done with an infusion pump during 90 minutes via the hypogastric artery at a drug dose of 1 mg./kg. for group 1 and 4 mg./kg. for group 2. To measure the serum doxorubicin concentration, blood samples were obtained from the subclavian vein 30, 60, 90, 120, 150 and 180 minutes after the beginning of infusion. For group 3, in addition to the aforementioned protocol, hemodialysis and direct hemoperfusion systems, connected in that order, were used concomitantly for 3 hours from the beginning of the infusion. Vascular access was provided by the femoral artery and vein, and blood samples were obtained from 3 different sites, that is the subclavian vein, and pre-artificial and post-artificial organs (dialyzer and column). Clearance of doxorubicin by hemodialysis and direct hemoperfusion was measured from the blood concentrations of doxorubicin (from the dialyzer and column) using the formula of Wolf and associates. 6 Immediately after the blood sampling at 90 minutes 2 of the 4 animals were sacrificed to measure tissue concentrations of doxorubicin in the bladder and prostate. Serum and tissue concentrations were measured by a fluorescence assay.7 Clinical study. We studied 11 patients with histologically proved bladder tumor, including 7 with measurable tumor. All patients were hospitalized between January 1979 and August 1982, and had not received any radiotherapy or chemotherapy before the study. The determination of the clinical stage of bladder cancer was made by excretory urography, bimanual examination of the pelvis with the patient under general anesthesia, computerized tomography (CT), lymphangiography and chest radiography. Bone and liver radionuclide scans were done when indicated clinically. Because of the need to evaluate this new therapy, transurethral resection of the tumor was not performed. The response criteria for evaluable disease were defined as 1) complete-complete regression of all measurable bladder tumor, 2) partial->50 per cent decrease in tumor size, 3) minor remission-25 to 50 per cent decrease in tumor size, 4) stable-<25 per cent decrease or increase in tumor size and 5) progression->25 per cent increase in tumor size. Mappings of all resected bladders were made according to the method of
MATERIALS AND METHODS
Experimental study. Doxorubicin (molecular weight 579.98) is a cytotoxic anticancer antibiotic that has a strong tissue affinity and is concentration-dependent. Mongrel dogs (body weight 10 to 15 kg.) were used in the experiments, which were performed under general anesthesia. The experimental design was the same as that used in the previously reported fundamental study on mitomycin C, while the dialysate supply system, dialyzer used for hemodialysis and petroleum charcoal column used for direct hemoperfusion also were of the same specifications.5 Each of the 3 experimental Accepted for publication July 1, 1983. Read at annual meeting of American Urological Association, Las Vegas, Nevada, April 17-21, 1983. Supported in part by grants-in-aid for Cancer Research from Ministry of Education, Science and Culture (57015067), Japan. 36
SHEI\l OT'}1ERAP~"i
Koss a.nd asso,('.iates. 8 of the acute ative vvas associates. 9 A summary of the patients is shown in table 1. Seven tumors were graded as T2 and 4 as T3. Patients 1, 5, 8 and 9 had recurrent tumor. All patients underwent regional chemotherapy 1 intra-arterial infusion with concomitant artificial organs (2 times for patient followed by radical cystectomy with excision of the regional lymph nodes and ilea! conduit urinary diversion 3 to 6 weeks later, except for patients 1 to 3 and 8 who underwent staged ilea! conduit urinary diversion before chemotherapy. Three chemotherapy regimens were tested: 1) 2 to 3 mg./kg. doxorubicin, 2) l mg./kg. mitomycin C, and 3) 10 mg. bleomycin daily on days 1 to 7 and 0.6 mg./kg. mitorn.ycin C on day 8. Doxorubicin and mitorn.ycin C were infused into both hypogastric arteries or the aortic bifurcation by Seldinger's method, while bleomycin was given by systemic infusion. Doxorubicin and mitomycin C were given continuously for 90 minutes using infusion pumps, and the artificial organs were used at the same time for 3 hours. Vascular access for the arterial line during hemodialysis and direct hemoperfusion was provided, either in the radial artery or inferior vena cava, and the blood was returned to the antecubital vein after it had passed through the artificial organs (fig. For direct hemoperfusion a petroleum charcoal column identical to that in the animal experiment was used. For hemodialysis the dialysate system was TM 101 (a sorbent-based recirculating dialysate regeneration system) with a hollow fiber dialyzer (C-DAK 1.3 artificial kidney, model 4), with a creatinine clearance at 200 ml. per minute and blood flow of 133 ml. per minute. To determine the rate of removal the artificial organs the serum concentrations of the drugs were measured at 30, 60, 90, 120, 150 and 180 minutes, and the total urinary concentration was measured for 3 hours from the beginning of treatment. Objective responses were evaluated 3 weeks after regional chemotherapy. RESULTS
In the experimental study the serum anticancer drug concentrations showed that the serum doxorubicin level in group 3 animals with the concomitant use of the artificial organs was the lowest, doxorubicin clearance of the artificial organs was higher when the serum drug level was high and the mean rate TABLE 1.
Pt. No.-Age-Sex
Clinical Stage
1-70-M
T3
I1
2-67-M
Tumor Grade*
Drug ( mg. per dose)
of clearance was 79.5 ml pei' minute 2). Tissue levels of doxorubicin in the bladder and prostate not decrease even when the artificial organs were used concomitantly (table 2). Serum concentrations of doxorubicin and mitomycin C in the clinical study were similar to those obtained in the animal experiments (figs. 3 and 4). The clearance to the time of completion of the drug infusion averaged 95. 7 ml. per minute for doxorubicin and 116. 7 ml. per minute for mitomycin C. Thus, mitomycin C was cleared at a higher rate. The removal rate varied greatly from 7.0 to 35.9 per cent of the administered dose of doxorubicin and 8.5 to 23.9 per cent of mitomycin C (table 3). The rate of removal of doxorubicin in patient 4 was 35.9 per cent of the administered dose, which was much higher than in the others. Hemodialysis was not used and 2 units of the column served as the artificial organs. The total urinary recovery rates up to 3 hours after administration were 2.8 to 9.0 per cent and 0.1 to 4.8 per cent of the administered doses of doxorubicin and mitomycin C, respectively (table 3). Objective responses (partial or complete) were obtained in 3 of 4 patients given doxorubicin and 1 of 3 given mitomycin C. The CT scan of patient 3 showed a large pelvic mass before therapy (fig. 5, A) but marked regression after therapy (fig. 5, B). Turn.or downstaging was seen in 4 of 5 patients treated with doxorubicin, 2 of 3 given mitomycin C, and 1 of 3 treated with bleomycin and mitomycin C. These 7 patients are alive with no evidence of recurrent tumor. Systemic toxicity was evaluated by a 5 grade system (0 through 4). Moderate and patchy alopecia (grade 2) as well as moderate to severe leukocytopenia (grades 2 to 4) was observed in all patients treated with doxorubicin, and thrombocytopenia was seen in only l patient. No cardiac, hepatic or renal toxicity was found in any of these patients and none complained of nausea or vomiting. Toxicity observed in the mitomycin C group was moderate (grades 1 and 2). Thrombocytopenia (grades 2 and 3) was noted in 2 patients treated with bleomycin and mitomycin C. In 1 patient treated with doxorubicin severe motor disturbances of the lower extremities were seen. Unexpected local toxicity was observed even by the concomitant use of this therapy, since 8 patients suffered mild localized pain that was considered to be the result of treatment. However, such severe reactions as necrosis or ulceration of the buttocks were not seen. A transient decrease of thrombocytes owing to adsorption of thrombocytes to direct hemoperfusion was seen in all patients but the degree was light and there were no clinical problems.
Clinical summary Artery Infused
Artificial Organs (ml./min.)
T3
III
Doxorubicin (100) Doxorubicin (150) Doxorubicin (150)
3-63-M
T2
III
Doxornbicin ( 150)
Bifurcation of aorta
4-65-M
T2
II
Doxorubicin (120)
Bifurcation of aorta
5-36-M
T3
II
Doxorubicin (150)
Bifurcation of aorta
6-69-M
T3
Squamous
Mitomycin C (60)
Rt. hypogastric
7-65-M
T2
III
Mitomycin C (50)
Bifurcation of aorta
8-74-M
T2
II
Mitomycin C (50)
Bifurcation of aorta
Hollow fiber kidney, column (150) Hollow fiber kidney, column (200) 2 units of column (150)t
9-52-M
T2
II
2 units of column (150)t
T2
III
Bilat. hypogastric
2 units of column (150)t
11-68-M
T2
II
Mitomycin C (42), bleomycin (70) Mitomycin C (34), bleomycin (70) Mitomycin C (38), bleomycin (70)
Bifurcation of aorta
10-73-M
Bilat. hypogastric
2 units of column (150)t
Patients 1 to 4 and 6 to 8 had measurable tumor.
* World Health Organization. t Hemosorba or DHP-1 column.
37
BLADilEi~, C1-\),JCER CONCOlV1Ir;AI\lT Vi!'TJ-I ARTIFICIAL ORGAI'
Bilat. hypogastric Bilat. hypogastric
Hollow fiber kidney, column (150) Hollow fiber kidney, column (150) Hollow fiber kidney, column (150) Hollow fiber kidney, column (150)t 2 units of column (150)t
Vascular Access (arterial line-venous line) Radial artery-antecubital vein Radial artery-antecubital vein Radial artery-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Radial artery-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein Inferior vena cava-antecubital vein
38
KAMIDONO AND ASSOCIATES TABLE 2.
Concentration of doxorubicin in bladder and prostate by group Bladder (mcg./gm.)
Group 1-1 mg./kg. doxorubicin* Group 2-4 mg./kg. doxorubicin* Group 3-4 mg./kg. doxorubicint
Trigone
Dome
Prostate (mcg./gm.)
9.9 54.5 58.7
4.1 38.6 31.8
9.1 80.7 75.0
* Intra-arterial infusion. t Intra-arterial infusion, hemodialysis and direct hemoperfusion.
A
~
~ a.
'QO
solid line : pre- artificial organs dotted line ; post-artificial organs 1 4 : patient : patient 2 0 ; patient 3
Intra-arterial infusion of P.DM
E
5. 0
•
0
E
arterial infusion of ADM or MMC ( to hypogastric artery or bifurcation of aorta)
:i:
: patient ; patient
0
<(
FIG. 1. Clinical design of regional chemotherapy given by intraarterial infusion with concomitant artificial organs. HD, hemodialysis. DHP, direct hemoperfusion. RA, radial artery. IVC, inferior vena cava. ADM, doxorubicin. MMC, mitomycin C.
.... 0
4 5
1.0
C:
..., ...,~ 0.5
.Q
C: Q)
0
C:
[}--{] Group 1 ( ADM 1 mg per kg) non-artificial organs <>--0 Group 2 ( ADM 4 mg per kg) non-artificial organs •·-eGroup 3 (ADM 4 mg per kg) artificial organs Intra- arterial infusion of ADM 1--=.=...:=.:..:.=.c.cc_c.c..:.:=.c..:::.:...==-.J (HD+DHP)
A
~ E
~
a.
5. 0
0
0
E
...
::, Q)
(/)
0. 1 0
8
(each group, n = 4)
'QO
0
E
,....._
:i:
·e ...
C:
0
Clearance of ADM
100
~ ; mean value
Q)
:: 1.0
a.
0
~-- - _..o-----~ - - --iJ,
C:
2 0.5
I
~C:
I
Q)
0
I
0
ti 1/
"" ,5 '
..- -----
//
C:
0
I
Q)
'
C:
-~,,
,
...
50
'
Q)
" '~
I'
E
n=5
0
__.o.._ - - - - - '-,
u
'
2
Q)
(/)
Clearance of ADM ®--0 : mean value ~ : range
8
100 C:
·e
,._
0
30
60
90
120
150
180
Time (min)
FIG. 3. A, serum concentration of doxorubicin (ADM) in blood samples of pre-artificial and post-artificial organs by patients. B, clearance of doxorubicin by artificial organs in 5 patients. Blood flow rate is 150 ml. per minute.
Q)
a.
"" ,5
50
n=4
Q)
0 C:
Q)
0
0
30
60
90
120
150
180
Time (min)
FIG. 2. A, serum concentration of doxorubicin (ADM) in subclavian vein by group in mongrel dogs. HD, hemodialysis. DHP, direct hemoperfusion. B, clearance of doxorubicin by artificial organs in group 3. Blood flow rate is 140 ml. per minute. DISCUSSION
The incidence of side effects caused by regional chemotherapy given by intra-arterial infusion is said to be lower generally compared to systemic administration. However, some anticancer drugs induce systemic toxicity equivalent to that seen during systemic administration .10• 11 Doxorubicin is one such antican-
cer drug. According to Chen and Gross, since doxorubicin is eliminated by biliary excretion and liver metabolism there would be no decrease in systemic toxicity but merely an increase in the regional drug concentration when it is infused in an organ other than the liver. 11 Since mitomycin C primarily is metabolized in the liver a similar mechanism is postulated. 12 From these points, the usefulness of concomitant hemodialysis and direct hemoperfusion during the intra-arterial infusion of anticancer drugs in heavy doses could be supported for the treatment of bladder cancer. Since experiments showed that the extra-regional serum drug concentrations were low because doxorubicin and mitomycin C were removed by the artificial organs, a decrease in systemic toxicity was expected. Objective responses were obtained in 75 per cent of the patients treated with doxorubicin and 33 per cent of those treated with mitomycin C. Of course, the trial number was small and comparison with other studies is difficult. However, our results are considered to be excellent compared to other reports. 13- 15 Although downstaging was observed in 7 of 11
CHEMOTHERAPY OF BLADDER CANCER CONCOMITANT WITH ARTIFICIAL ORGANS
...
solid line : pre-artificial organs dotted line : post-artificial organs
8. Ill)
0.5
1 0 :::!E :::!E
0
• •
: patient : patient
6 7
•
: patient
8
0. 1
C
:8
39
patients (64 per cent) there was a small discrepancy between the downstaging and objective responses . The purpose of chemotherapy in our procedure is not to sterilize the primary tumor but to reduce systemic toxicity to permit an early radical operation following chemotherapy. The mean preoperative interval was 30 days and such a relatively long interval was partly owing to careful evaluation of the systemic toxicity in relation to the appearance of side effects. 12
~ 0.05 5i0 C
0 0
E
2
Jl
150
B
Clearance of MMC mean value
C!)ooo0 ·
100 L Q)
Q.
! Q)
g
50
f
0
0
30
60
90
120
150
180
Time (min)
FIG. 4. A, serum concentration of mitomycin C (MMC) in blood samples of pre-artificial and post-artificial organs by patient. B, clearance of mitomycin C by artificial organs in 3 patients. Blood flow rates are 150 to 200 ml. per minute. TABLE 3.
Results of preoperative chemotherapy Survival (mos.)
Removal Rate of Extra-regional Anticancer Drugs Mg.(%)
Urinary Recovery in ;a,3 Hrs. Mg.(%)
Hair, local pain Leukocytes
48, no evidence of disease
9.2 (9.2) 19.3 (12.9)
13.5 (9.0)
2 3
Hair, local pain Leukocytes
11, dead
14.6 (9.7)
5.5 (3.7)
pT2 (T3)
2 3 4
Hair Local pain Leukocytes
41, no evidence of disease
10.5 (7.0)
7.6 (5.1)
4
pTl (T2)
1 2
Platelets Hair, local pain, leukocytes
18, no evidence of disease
43.1 (35.9)
3.3 (2.8)
6
pTl (T2)
2 3 4
Hair Leukocytes, local pain Neurotoxicity
12, no evidence of disease
36.6 (24.4)
11.3 (7.5)
4
pT4 (T3)
1
Serum glutamic pyruvic transaminase, nausea Serum glutamic oxaloacetic transaminase, local pain
5, dead
5.1 (8.5)
0.7 (1.2)
26, no evidence of disease
6.2 (12.4)
2.4 (4.8)
7, no evidence of disease
2.8 (10.0)
0.6 (2.1)
11, no evidence of disease
3.9 (9.3)
0.9 (2.1)
Objective Response*
Interval to Operation (wks.)
Pathologic Stage (clinical stage)
Grade of Toxicity
1
Partial
4
pTl (T3)
2 3
2
Partial
3
pT3 (T3)
3
Partial
4
4
Minor remission
Pt. No.
5
6
Partial
FIG. 5. Patient 3. CT scans show response to regional chemotherapy of pelvic lesion that was proved at operation. A, before chemotherapy. B, after chemotherapy.
2
Complications
7
Stable
6
pTl (T2)
1
Local pain, platelets
8
Stable
6
pTl (T2)
1
Leukocytes
9
3
pT2 (T2)
10
3
pT2 (T2)
1 3
Leukocytes Platelets
7, dead
6.7 (19.7)
0.4 (0.1)
11
3
pTl (T2)
1 2
Leukocytes, local pain Platelets
6, no evidence of disease
9.1 (23.9)
0.3 (0.1)
None
* Partial response-50 per cent by CT scan in the sum of the products of S::2 perpendicular diameters, minor remission-25 to 49 per cent decrease in tumor size and stable-25 per cent decrease in tumor size.4
40
KAMIDONO AND ASSOCIATES
From the difference in the serum drug concentrations in the animals with and without the use of artificial organs,5 the amount of anticancer drug removed in the clinical study and the clinical results of side effects, our treatment certainly is considered to be useful. However, further extensive studies are required because removal of the anticancer drugs by the artificial organs did not reduce necessarily the incidence of the side effects. We are continuing this method because the amount of drug removed with a column of 2 units in patient 4 was reduced considerably. A shortening of the preoperative interval also may be expected. Despite a higher rate of clearance of mitomycin C by the artificial organs compared to that of doxorubicin, the latter group showed a greater quantity of drug removed. This finding probably was owing to the higher dose of doxorubicin and the higher serum concentrations achieved. The artery used for infusion or the location of the vascular access varied slightly among the patients but this did not result in marked differences in objective responses or systemic and local toxicity. REFERENCES 1. Whitmore, W. F., Jr., Batata, M.A., Ghoneim, M.A., Grabstald, H. and Una!, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. 2. Skinner, D. G.: Current perspectives in the management of highgrade invasive bladder cancer. Cancer, suppl. 7, 45: 1866, 1980. 3. Boileau, M.A., Johnson, D. E., Chan, R. C. and Gonzales, M. 0.: Bladder carcinoma: results with preoperative radiation therapy and radical cystectomy. Urology, 16: 569, 1980. 4. Yagoda, A.: Chemotherapy of metastatic bladder cancer. Cancer, suppl. 7, 45: 1879, 1980. 5. Kamidono, S., Hamami, G., Fujii, A. and Ishigami, J.: A fundamental study of regional chemotherapy given by intraarterial infusion with concomitant hemodialysis and hemoperfusion. Invest. Urol., 19: 176, 1981. 6. Wolf, A. V., Remp, D., Kiley, J. E. and Currie, G. D.: Artificial kidney function: kinetics of hemodialysis. J. Clin. Invest., 30: 1062, 1951. 7. Rosso, R., Ravazzoni, C., Esposito, M., Sala, R. and Santi, L.: Plasma and urinary levels of adriamycin in man. Eur. J. Cancer, 8: 455, 1972. 8. Koss, L. G., Tiamson, E. M. and Robbins, M.A.: Mapping cancerous and precancerous bladder changes. A study of the urothelium in ten surgically removed bladders. J.A.M.A., 227: 281, 1974. 9. Miller, A. B., Hoogstraten, B., Staquet, M. and Winkler, A.: Reporting results of cancer treatment. Cancer, 47: 207, 1981. 10. Haskell, C. M., Eilber, F. R. and Morton, D. L.: Adriamycin (NCS123127) by arterial infusion. Cancer Chemother. Rep., part 3, 6: 187, 1975. 11. Chen, H. S. and Gross, J. F.: Intra-arterial infusion of anticancer drugs: theoretical aspects of drug delivery and review of responses. Cancer Treat. Rep., 64: 31, 1980. 12. Murinson, D. S.: Clinical pharmacology of antineoplastic agents.
In: Practical Cancer Chemotherapy. Edited by S. N. Rosenthal and J.M. Bennett. New York: Medical Examination Publishing Co., Inc., chapt. 2, p. 14, 1981. 13. Pavone-Macaluso, M.: Chemotherapy of vesical and prostatic tumours. Brit. J. Urol., 43: 701, 1971. 14. Middleman, E., Luce, J. and Frei, E., III: Clinical trials with adriamycin. Cancer, 28: 844, 1971. 15. Kraybill, W. G., Harrison, M., Sasaki, T. and Fletcher, W. S.: Regional intra-arterial infusion of adriamycin in the treatment of cancer. Surg., Gynec. & Obst., 144: 355, 1977. EDITORIAL COMMENTS The clinical experience is small but impressive. Cisplatin might have been used after animal experimentation, since most of the agent is taken up by the first capillary bed when given intra-arterially during 48 hours. It is important to have these techniques in place but the real problem is that we do not understand the fundamentals of the primary and/or metastatic growth rates nor do we presently have effective drugs for any adjuvant role. George R. Prout, Jr. Department of Urology Massachusetts General Hospital Boston, Massachusetts The authors have presented an interesting feasibility study. Their data reveal a significant reduction in serum concentration of drug achieved by hemodialysis and direct hemoperfusion. The tissue levels achieved in the bladder and prostate were not compromised using hemodialysis and direct hemoperfusion (table 2 in article). Systemic drug toxicity was not eliminated. Patient 4, in whom a column of 2 units was used, achieved a significant increase in the amount of drug removed. While the data do not allow any statement regarding therapeutic efficacy, their approach is novel and may merit controlled clinical trials. Kenneth B. Cummings Division of Urology Department of Surgery University of Wisconsin Hospital and Clinics Madison, Wisconsin REPLY BY AUTHORS We completed animal experiments with cisplatin, which revealed that about 50 per cent of the total administration dosage was absorbed and removed from the body with direct hemoperfusion. Based on these experimental data a clinical study in which heavy dosage of cisplatin administration is made using direct hemoperfusion is under trial, and it shows fairly good results in the antineoplastic effects against bladder cancer and the reduction of the systemic toxicity of the drug. The administration dosage of either 3.0 mg. doxorubicin or 1.0 mg. mitomycin C per kg. body weight has been considered to be a lethal dosage but all patients were alive for at least 4 months. Thereafter, 3 patients died of cancer and not drug toxicity. Thus, we believe that hemodialysis and direct hemoperfusion must have reduced the systemic toxicity of the agent to some extent.