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Treatment of Renal Cancer Patients by Transcatheter Embolization and its Effects on Lymphocyte Proliferative Responses
0022-5347/83/1307-0024$02.00 /0 Vol. 130, July Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1983 by The Williams & Wilkins Co.
TREATMENT OF RENAL CANCER PATIENTS BY TRANSCATHETER EMBOLIZATION AND ITS EFFECTS ON LYMPHOCYTE PROLIFERATIVE RESPONSES HIROSHI NAKANO, HIROMI NIHIRA
AND
TETSUYA TOGE
From the Departments of Urology and Surgery, Research Institute for Nuclear Medicine and Biology, Hiroshima University School of Medicine, Hiroshima, Japan ABSTRACT
The effects of transcatheter embolization on lymphocyte proliferation in patients with renal cancer were investigated. Prognosis was good in 12 patients who underwent preoperative transcatheter embolization and 2 of 5 patients with distant metastases survived for 2 years or more. The remaining 9 patients underwent transcatheter embolization as a conservative procedure and 4 of 7 with distant metastases survived more than 1 year. Lymphocyte response to phytohemagglutinin before treatment in the presence of autologous or homologous serum was significantly lower in all patients than in healthy persons (p less than 0.01 and less than 0.05, respectively). The response after transcatheter embolization decreased slightly only in the presence of autologous serum for a short interval but recovered to the pre-treatment level 1 month after embolization. However, only in the presence of autologous serum was the response significantly higher at 2 months after nephrectomy than before treatment in patients who underwent preoperative transcatheter embolization (p less than 0.05). The serum inhibitory factor levels changed in inverse proportion to the post-treatment lymphocyte response. In patients who underwent preoperative transcatheter embolization the serum inhibitory factors essentially disappeared 2 months after nephrectomy. of OK-432 (5 K.E.* every week) and/or PSK, a protein bound polysaccharide extracted from Coriolous versicolor Quel in Basidiomycetes (3 gm. per day) for a short interval. Hormone therapy consisted of 50 to 100 mg. progesterone daily during 1 to 12 months. One patient received doxorubicin and radiation therapy for a bone metastasis of the lower extremity, which subsequently was removed. Lymphocyte culture. Lymphocyte culture was performed by the microculture method described previously. 3 The results. were expressed in counts per minute.
There have been reports of progressive arrest of primary lesions during a long interval, or a gradual development or natural disappearance of distant metastatic lesions ~10 years after surgical removal of the primary lesion in patients with renal cancer. Therefore, the prognosis of this entity is considered to have a close relationship to the immunological defense of the host. 1 Previously, we showed that catheter embolization of the renal artery in patients with renal cancer caused necrosis of tumor tissues, and lymphocyte infiltration and formation of fibrous membranes around the residual tumor tissues, which were presumably owing to host immunity. 2 We herein investigate the prognosis of patients with renal cancer undergoing embolization of the renal artery and its effects on the immunological reactivity.
TABLE
1.
Results of transcatheter embolization and surgery in patients with renal cancer
Case No.-Age-Sex (classification*) Nl-55-M (T3N4+MldVl) N2-64-M (T3NO-MOV1) N3-72-F (T3NO-MlbVO) N4-43-M (T3NO-MOVO) N5-53-M (T3NxMOVO) N6-64-F (T3NrMlcVo) N7-43-M (T3Nl-MOVO) N8-73-M (T3NO+MOVO) N9-38-F (T2NxMOVO) Nl0-56-F (T3N2+MOVO) Nll-61-M (T3N3+MldVO)
MATERIALS AND METHODS
Patients. The 14 men and 7 women with renal cancer ranged from 38 to 87 years old, with a mean age of 58.2 years. A total of 24 embolization procedures was done. N ephrectomy subsequent to embolization was done in 12 of 21 patients and embolization only was performed in the remaining inoperable 9 as a conservative procedure (tables 1 and 2). Lymphocyte response to phytohemagglutinin was determined before and after embolization in 16 patients and in 93 age-matched healthy volunteers (controls). Transcatheter arterial embolization. After conventional angiography of the kidneys was done the affected renal artery was obstructed by gelatin sponge or 1-isobutyl-2-cyanoacrylate. Treatment after embolization. Of 21 patients 12 underwent nephrectomy between 3 hours and 34 days (mean 16 days) after embolization. After embolization or subsequent nephrectomy 19 patients were treated by chemotherapy, immunotherapy and hormone therapy independently or in combination for a short interval. Chemotherapy consisted of doxorubicin only (40 to 60 mg. every 3 to 4 weeks), or 5-fluorouracil (500 mg.) and cytosine arabinoside (40 mg.) in combination. Immunotherapy consisted
Nl2-63-M (T4NxMlcVl)
Treatment After Embolization Nephrectomy, chemotherapy and immunotherapy Nephrectomy, hormone therapy and immunotherapy Nephrectomy and hormone therapy Nephrectomy, hormone therapy and immunotherapy Nephrectomy and hormone therapy Nephrectomy, chemotherapy and hormone therapy Nephrectomy Nephrectomy Nephrectomy, chemotherapy and immunotherapy Nephrectomy and chemotherapy Nephrectomy, chemotherapy, immunotherapy and hormone therapy Nephrectomy, chemotherapy and immunotherapy
Survival After Embolization (mos.) Dead of disease (2) Alive without disease (63) Alive with disease (58) Alive without disease (54) Alive without disease (53) Dead of disease (49) Alive without disease (52) Alive without disease (46) Alive without disease (42) Alive without disease (40) Dead of disease (9) Dead of disease (9)
• Tumor, nodes and metastasis classification.
*K.E.-Klinische einheit (1 K.E. corresponding to 0.1 mg. dried cells).
Accepted for publication November 24, 1982. 24
TRANSCATHETER EMBOLIZATION FOR RENAL CANCER TABLE
2. Results of transcatheter embolization as palliative measures in patients with renal cancer
Case No.-Age-Sex (classification*) Pl-58-M (T3N2MldV2) P2-60-M (TlN2MldVO) P3-53-M (T3NxMOV2) P4-53-F (T4NxMldVO) P5-54-F (T3NxMldV1) P6-87-M (T4N2MOV1) P7-57-F (T3NxMlcVO) PS-63-M (T3NxMlcVO) P9-52-M (T4N2MlcV2)
Therapy After Ernbolization
Clinical Effects (Kamofsky's criteria)
Survival After Embolization (mos.)
Chemotherapy and immunotherapy, then immunotherapy and hormone therapy
lA
Dead of disease (16)
Im,munotherapy and. hormone therapy
lB
Dead of disease (6)
Hormone therapy
lC
Dead of disease (35)
Irnmunotherapy and hormone therapy
00
Dead of disease (1.5)
Hormone therapy
00
Dead of disease (2.5)
Hormone therapy
lC
Dead of disease (18)
Chemotherapy and irradiation for metastasis, thigh amputationt Hormone therapy
lC
Dead of disease (31)
lB
Dead of disease (15)
Immunotherapy
lA
Dead of disease (12)
* Tumor, nodes and metastasis classification.
"t Amputation of left lower extremity with a bone metastasis after radiation therapy.
•NCU~u,_,,,,,.UCVU.UH sti.mulation serum was formula percentage of u1,mvu,w·u (A ·- B)/B X 100, A is the lymphocyte response to tohe·maggl1LJ.t1m1n in the presence of homologous serum and of v-,.-, ,-v,v serum. When A was Iower than B the 1;;1J::,:t,~'t1c,:: value was judged to be 0 The measured values were analyzed statistically test. The values were the F test unequal randomization. All standard deviation,
r@
0
RESULTS
P1re,on<>r,c,trn·P
embolization was done
11 Of Wh0ffi had 1).4 All 7 f'O.CiCHCC>
0
nw,arP<:~HTP
metastases before embolization are for a survival of 40 to 60 months, with an average of 50 months. The, c,,ua.uu,un 5 patients with distant metastases before embolization had an survival of 25.9 months: 4 died of cancer 2 to 49 after ;cu,v~,uL,O.v7CV.U but l (N3) remains alive at 58 rnonths. va:tunts who underwent renal cancer eniboliIn 9 patie:nts (mean age 60 rnr,r«,r,,,,,m, .. cancer with a wide range of metastases conservative treatment was done after embolization (table 2). In 7 of these 9 (78 per cent) response to of ?;lA was noted as judged by Kamofsky's criteria. 5 The 2 patients witlh locally extended infiltration without distant metastases before embolization survived for 18 to 35 of 26.5 months. Six ''"''""'°'""" .yrnp,ncic,rte responsiveness to ptty1:011eim11g1~lc1U:mn was 16 patients who underwent renal. cancer embolization, The response values were ± counts per minute in the presence of autologous serum and 21,379 ± 5,669 counts per minute in the presence of homologous serum before embolization 1). Statistically significant differences were noted rmnn,ar~·n to the controls (p <0.01 and <0.05, respecbut there was no significant difference in the response values between patients with and without distant metastases. The values 2 weeks after embolization decreased to a level of 14,437 ± 11,304 counts per minute in the presence of aucvJtu~,vut
----+------~------. . ---~---~---·< w. 1 m. 2 m, m. after embolizalion
after
Time a.Her treatmeni
B 50
~
~40 E
CL
u
Pre.
2w.
1m.
2m.
after embolization
1m.
2m.
~4m.
after nephrectomy
Time after treatrnent Fm. 1. Lymphocyte response to phytohemagglutinin (counts minute) in presence of autologous (A) and homologous (B) serum patients with renal cancer before and after transcatheter embolization of renal artery of tumorous kidney and after nephrectomy. Horizontat bars indicate mean percentage and vertical bars indicate ± 1 standard deviation. Shaded areas indicate normal range ± l standard deviation of 94 healthy volunteers.
ther to 25,546 ± 9,296 and 24,705 ± 5,875 counts per uuuuc•c, respectively, in the presence of homologous serum. However, there was no significant difference between values before and after embolization.
26
NAKANO, NIHIRA AND TOGE
80 C 0
-
;g 6
.c
•
C
0 1:40 QI
I:!
•
t
Cl/
a.
20
0
I •
Pre.
2 w. 1 rn. 2 rn. after embolization
1 rn. 2 rn. 2;4m. after nephrectorny
Time atter treatment FIG. 2. Percentage of inhibition of lymphocyte response to phytohemagglutinin by autologous serum from patients with renal cancer before and after transcatheter embolization of renal artery of tumorous kidney and after nephrectomy. Horizontal bars indicate mean and vertical bars indicate ± 1 standard deviation.
In contrast, in patients who underwent nephrectomy within 5 weeks after embolization the response values increased after nephrectomy in the presence of either autologous or homologous serum, and there was a significant difference only between the high value of 32,890 ± 12,070 counts per minute 2 months after nephrectomy and the values before embolization in the presence of autologous serum (p <0.05). Changes of serum inhibitory factor levels after embolization. The changes of serum inhibitory factor levels after renal cancer embolization were examined. The level before embolization was 20.6 ± 19.8 per cent and 2 weeks after embolization it was 43.4 ± 27.4 per cent, being higher in 5 of 6 patients examined but no significant increase was observed (fig. 2). The subsequent inhibitory rates were 27.6 ± 15.3 and 21.1 ± 15.4 per cent l and 2 months after embolization, respectively, with no difference between rates before and after embolization. On the contrary, in patients who underwent nephrectomy within 5 weeks after embolization the rate decreased remarkably, that is the inhibitory rate decreased to 18.2 ± 23. 7 per cent l month after nephrectomy, 5.9 ± 10.0 per cent 2 months after nephrectomy and 1.9 ± 4.3 per cent ~4 months after nephrectomy. There was a significant difference between the value 2 months postoperatively and that before embolization (p <0.05). Furthermore, inhibition oflymphocyte response by autologous sera was not observed in 4 of 5 patients for ~4 months after nephrectomy subsequent to embolization. Consequently, nephrectomy may cause a decrease in serum inhibitory factors. DISCUSSION
One of the causes responsible for spontaneous regression of primary and metastatic lesions in renal cancer is considered to be ischemia ascribable to circulatory disturbance in the tumor. Bloom reported ligation of a renal artery in a patient with renal cancer but no effect of the ligature on the metastatic lesions was observed. 1Obstruction ofrenal blood supply by this method seems inadequate because blood supply from collateral circulation and renal veins is considered to be present. Renal cancer embolization is considered to differ from ligation because it is possible to occlude the peripheral arteries under the control of that artery. Therefore, it was surmised that diffuse necrosis in the primary lesion leads to the regression of the metastatic lesions. 6 In regard to the clinical effects we have reported that embolization of renal cancer is efficacious as treatment before nephrectomy and also as conservative therapy in patients who cannot undergo nephrectomy from the therapeutic viewpoint of inhibition of the blood supply to the tumor. 2 From histolog-
ical findings of renal cancer resected after embolization it has been assumed that embolization is associated with necrosis of tumor tissue, promotion of lymphocyte infiltration and formation of fibrous membranes around the residual tumor tissue. 2 Generally, the inhibitory response to proliferative growth of cancer cells involves histologically proliferation of connective tissue of the interstitial cells and infiltration of various inflammatory cells in tumor tissue,7 and formation of fibrous membranes around the residual tumor cells. 8 It is said that the stronger the interstitial response the better the prognosis, especially since the lymphocyte infiltration represents the local defense mechanism and immunological pheQomenon. 7 In our study of patients with metastatic renal cancer combined embolization and nephrectomy enabled 2 of 5 patients (40 per cent) to survive ~2 years, while 4 of 7 (approximately 57 per cent) survived ~l years with embolization therapy only. These results accord a better prognosis than that reported previously. 9- 11 Our results are considered to be related to the presence of the aforementioned interstitial reaction. In this regard, Helmstein first devised hydrostatic pressure therapy for bladder tumors and elucidated the immunological mechanism between tumor tissues and tumor-bearing host. 12 Since infiltration of lymphocytes and plasma cells is a histological response to hydrostatic pressure therapy it has been suggested that this reaction participates in the immunological response. 12 There is evidence that specific immunological responses occur through the mediation of substances originating from the destroyed cells. 13 Our results and those of a previous study14 show that cell-mediated immunity in patients with renal cancer is lower than that of healthy subjects. However, there is little information about the immunological reaction after transcatheter arterial embolization in patients with renal cancer and the mechanism of the effects of this procedure still is unclear. It seems that the adverse effects of embolization on the immunological system are comparatively mild and occur only for extremely short intervals. It is likely that the patients are in a transient cachectic condition2 owing to unknown substances, such as massive toxic substances released temporarily into the circulation from the necrotic tissues of renal cancer, and that a part of the defect of the immunological response is caused by cachexia 15 and an increase of inhibitory factors in the serum. 3 In patients with renal cancer who underwent nephrectomy only cell-mediated immunity using the microtoxicity assay is reported to increase significantly compared to that of preoperative patients.16 However, the assay was done in the presence of homologous serum. In the presence of autologous serum the immunity after nephrectomy became lower than that of preoperative patients in most cases. It has been reported that the number of T cells after nephrectomy decreased transiently and did not increase significantly compared to that before nephrectomy during subsequent long-term observation. 17 However, in patients who underwent combined therapy with embolization and nephrectomy there was a significant increase in T cells 14 and also in the responsiveness to phytohemagglutinin in the presence of autologous serum in our study. Although the patients treated by palliative embolization were inoperable and in the terminal stage, and the period of immunotherapy was extremely short in most cases, lymphocyte responsiveness was maintained at the level before embolization or improved during long-term observation. Consequently, it seems that improved prognosis in our series paralleled improved immunity after embolization. High inhibitory factors are considered to be present in a 2 globulin 17 and immunoglobulin G 13 fractions. In our study the serum inhibitory factors were determined by calculation based on the difference in lymphocyte response value to phytohemagglutinin in patients with renal cancer when adding autologous serum and healthy serum. The patients with distant metastases had a significant increase in the inhibitory factor level before embolization than those without metastases. The increase in
TRANSCATHETER JEMBOLIZATION FOR RENAL CANCER
factors of autologous serum on lymphocyte responsiveness in who underwent renal cancer embolization may be assumed to have been affected by toxic substances from the tumor and entering the circulatory system necrotic tissues of the primary lesion. The """'""',."'" levels tended to be high for a certain interval after decreased significantly from 2 when nephrectomy was done within ~u«vovrn,-,.N,,,. This fact shows that an irre-
27
5. Karnofsky, D. A.: Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin. Pharm. Ther., 2: 709, 1961. 6. Sophocles, A. M., Jr. and Nadler, S. H.: Immunologic aspects of cancer. Surg., Gynec. & Obst., 133: 321, 1971. 7. Enjoji, M.: Mesenchymal reaction in tumor-bearing host. In: Cancer Immunotherapy. Edited H. Kobayashi and T. Tachibana. Tokyo: Asakura Shoten, 2, p. 289, 1974. 8. Ohkita, K., Matsumura, Y., T. and Katayama, Y.: A statistical and pathological study on the tumors of the upper urinary tracts with some follow-up studies. Nishinihon J. UroL, 31: 343, 1969.
embolization and ntonh,re>l'i-,,mu the inhibitory factor serve as an index of an efficacy of '" h " " ~ " ' " estimation of the prognosis. In
REFERENCES 1. Bloom, H.J. G.: Hormone-induced and spontaneous regression of
metastatic renal cancer. Cancer, 32: 1066, 1973. Nakano, H.: Study on transcatheter embolization for renal carcinoma. 2nd Report-host immune rntm(m,,e after transcatheter embolization. J. Urnl., 71: 913, 3. Ikeda, Senoo, N., Niimoto, M. and Hattori, T.: Lvmrlhc,cvte responsiveness to phytohemagglutinin (FHA) and serum m1nb1tor, effect in patients with gastric cancer. Jap. J. Surg., 6: 157, 1976. 4. Wallace, D. M., Chisholm, G. D. and Hendry, W. F.: T.N.M. classification for urological tumours (U.I.C.C.)-1974. Brit. J. Urol.., 47: 1, 1975.
9. Skinner, D. G. and deKernion, J. B.: Clinical manifestations and treatment of renal parenchymal tumors. In: Genitourinary Can-· cer. Philadelphia: W. B. Saunders Co., cha.pt. 5, p. 107, 1978. 10. Katz, S. A. and Davis, J. E.: Renal adenocarcinoma: prognostics and treatment reflected by survival. Urology, HI: 10, 1977. 11. Middleton, R. G.: Surgery for metastatic renal cell carcinoma. J. Urol., !ll7: 973, 1967. 12. Helmstein, K.: Treatment of bladder carcinoma pressure technique. Report on 43 cases. Brit. J. 1972. 13. Bubenik, J., Perlmann, P., Helrnstein, K. and Moberger, G.: Cellular and humoral immune responses to human urina,y bladde,- c,a. cinomas. Int. J. Cancer, 5: 310, 1970. 14. Carmignani, G., Belgrano, E., Puppo, P. and Comaglia, P.: T and B
lymphocyte levels in :renal cancer patients: influence of preoperative transcatheter embolization and radical nephrectomy. ,J Urol., 118: 941, 1977. 15. Chabner, B. A., DeVita, V. T., Livingston, D. M. and Oliverio, V. T.: Abnormalities of tryptophan metabolism and doxal phosphate in Hodgkin's disease. New Engl. 838, 1970. 16. Montie, J. E., Straffon, R. A., Deodchar, S. D. and Barna, .El.. fo vitro assessment of cell-mediated immunity in patients with renal cell carcinoma. J. Urol., 115: 239, 1976. 17. Morales, A. and Eidinger, D.: Immune :reactivity in renal cancer: a sequential study. J. Urol., 115: 510, 1976.
j
THE JOURNAL OF UROLOGY
Copyright© 1983 by The Williams & Wilkins Co.
TREATMENT OF RENAL CANCER PATIENTS BY TRANSCATHETER EMBOLIZATION AND ITS EFFECTS ON LYMPHOCYTE PROLIFERATIVE RESPONSES HIROSHI NAKANO, HIROMI NIHIRA
AND
TETSUYA TOGE
From the Departments of Urology and Surgery, Research Institute for Nuclear Medicine and Biology, Hiroshima University School of Medicine, Hiroshima, Japan ABSTRACT
The effects of transcatheter embolization on lymphocyte proliferation in patients with renal cancer were investigated. Prognosis was good in 12 patients who underwent preoperative transcatheter embolization and 2 of 5 patients with distant metastases survived for 2 years or more. The remaining 9 patients underwent transcatheter embolization as a conservative procedure and 4 of 7 with distant metastases survived more than 1 year. Lymphocyte response to phytohemagglutinin before treatment in the presence of autologous or homologous serum was significantly lower in all patients than in healthy persons (p less than 0.01 and less than 0.05, respectively). The response after transcatheter embolization decreased slightly only in the presence of autologous serum for a short interval but recovered to the pre-treatment level 1 month after embolization. However, only in the presence of autologous serum was the response significantly higher at 2 months after nephrectomy than before treatment in patients who underwent preoperative transcatheter embolization (p less than 0.05). The serum inhibitory factor levels changed in inverse proportion to the post-treatment lymphocyte response. In patients who underwent preoperative transcatheter embolization the serum inhibitory factors essentially disappeared 2 months after nephrectomy. of OK-432 (5 K.E.* every week) and/or PSK, a protein bound polysaccharide extracted from Coriolous versicolor Quel in Basidiomycetes (3 gm. per day) for a short interval. Hormone therapy consisted of 50 to 100 mg. progesterone daily during 1 to 12 months. One patient received doxorubicin and radiation therapy for a bone metastasis of the lower extremity, which subsequently was removed. Lymphocyte culture. Lymphocyte culture was performed by the microculture method described previously. 3 The results. were expressed in counts per minute.
There have been reports of progressive arrest of primary lesions during a long interval, or a gradual development or natural disappearance of distant metastatic lesions ~10 years after surgical removal of the primary lesion in patients with renal cancer. Therefore, the prognosis of this entity is considered to have a close relationship to the immunological defense of the host. 1 Previously, we showed that catheter embolization of the renal artery in patients with renal cancer caused necrosis of tumor tissues, and lymphocyte infiltration and formation of fibrous membranes around the residual tumor tissues, which were presumably owing to host immunity. 2 We herein investigate the prognosis of patients with renal cancer undergoing embolization of the renal artery and its effects on the immunological reactivity.
TABLE
1.
Results of transcatheter embolization and surgery in patients with renal cancer
Case No.-Age-Sex (classification*) Nl-55-M (T3N4+MldVl) N2-64-M (T3NO-MOV1) N3-72-F (T3NO-MlbVO) N4-43-M (T3NO-MOVO) N5-53-M (T3NxMOVO) N6-64-F (T3NrMlcVo) N7-43-M (T3Nl-MOVO) N8-73-M (T3NO+MOVO) N9-38-F (T2NxMOVO) Nl0-56-F (T3N2+MOVO) Nll-61-M (T3N3+MldVO)
MATERIALS AND METHODS
Patients. The 14 men and 7 women with renal cancer ranged from 38 to 87 years old, with a mean age of 58.2 years. A total of 24 embolization procedures was done. N ephrectomy subsequent to embolization was done in 12 of 21 patients and embolization only was performed in the remaining inoperable 9 as a conservative procedure (tables 1 and 2). Lymphocyte response to phytohemagglutinin was determined before and after embolization in 16 patients and in 93 age-matched healthy volunteers (controls). Transcatheter arterial embolization. After conventional angiography of the kidneys was done the affected renal artery was obstructed by gelatin sponge or 1-isobutyl-2-cyanoacrylate. Treatment after embolization. Of 21 patients 12 underwent nephrectomy between 3 hours and 34 days (mean 16 days) after embolization. After embolization or subsequent nephrectomy 19 patients were treated by chemotherapy, immunotherapy and hormone therapy independently or in combination for a short interval. Chemotherapy consisted of doxorubicin only (40 to 60 mg. every 3 to 4 weeks), or 5-fluorouracil (500 mg.) and cytosine arabinoside (40 mg.) in combination. Immunotherapy consisted
Nl2-63-M (T4NxMlcVl)
Treatment After Embolization Nephrectomy, chemotherapy and immunotherapy Nephrectomy, hormone therapy and immunotherapy Nephrectomy and hormone therapy Nephrectomy, hormone therapy and immunotherapy Nephrectomy and hormone therapy Nephrectomy, chemotherapy and hormone therapy Nephrectomy Nephrectomy Nephrectomy, chemotherapy and immunotherapy Nephrectomy and chemotherapy Nephrectomy, chemotherapy, immunotherapy and hormone therapy Nephrectomy, chemotherapy and immunotherapy
Survival After Embolization (mos.) Dead of disease (2) Alive without disease (63) Alive with disease (58) Alive without disease (54) Alive without disease (53) Dead of disease (49) Alive without disease (52) Alive without disease (46) Alive without disease (42) Alive without disease (40) Dead of disease (9) Dead of disease (9)
• Tumor, nodes and metastasis classification.
*K.E.-Klinische einheit (1 K.E. corresponding to 0.1 mg. dried cells).
Accepted for publication November 24, 1982. 24
TRANSCATHETER EMBOLIZATION FOR RENAL CANCER TABLE
2. Results of transcatheter embolization as palliative measures in patients with renal cancer
Case No.-Age-Sex (classification*) Pl-58-M (T3N2MldV2) P2-60-M (TlN2MldVO) P3-53-M (T3NxMOV2) P4-53-F (T4NxMldVO) P5-54-F (T3NxMldV1) P6-87-M (T4N2MOV1) P7-57-F (T3NxMlcVO) PS-63-M (T3NxMlcVO) P9-52-M (T4N2MlcV2)
Therapy After Ernbolization
Clinical Effects (Kamofsky's criteria)
Survival After Embolization (mos.)
Chemotherapy and immunotherapy, then immunotherapy and hormone therapy
lA
Dead of disease (16)
Im,munotherapy and. hormone therapy
lB
Dead of disease (6)
Hormone therapy
lC
Dead of disease (35)
Irnmunotherapy and hormone therapy
00
Dead of disease (1.5)
Hormone therapy
00
Dead of disease (2.5)
Hormone therapy
lC
Dead of disease (18)
Chemotherapy and irradiation for metastasis, thigh amputationt Hormone therapy
lC
Dead of disease (31)
lB
Dead of disease (15)
Immunotherapy
lA
Dead of disease (12)
* Tumor, nodes and metastasis classification.
"t Amputation of left lower extremity with a bone metastasis after radiation therapy.
•NCU~u,_,,,,,.UCVU.UH sti.mulation serum was formula percentage of u1,mvu,w·u (A ·- B)/B X 100, A is the lymphocyte response to tohe·maggl1LJ.t1m1n in the presence of homologous serum and of v-,.-, ,-v,v serum. When A was Iower than B the 1;;1J::,:t,~'t1c,:: value was judged to be 0 The measured values were analyzed statistically test. The values were the F test unequal randomization. All standard deviation,
r@
0
RESULTS
P1re,on<>r,c,trn·P
embolization was done
11 Of Wh0ffi had 1).4 All 7 f'O.CiCHCC>
0
nw,arP<:~HTP
metastases before embolization are for a survival of 40 to 60 months, with an average of 50 months. The, c,,ua.uu,un 5 patients with distant metastases before embolization had an survival of 25.9 months: 4 died of cancer 2 to 49 after ;cu,v~,uL,O.v7CV.U but l (N3) remains alive at 58 rnonths. va:tunts who underwent renal cancer eniboliIn 9 patie:nts (mean age 60 rnr,r«,r,,,,,m, .. cancer with a wide range of metastases conservative treatment was done after embolization (table 2). In 7 of these 9 (78 per cent) response to of ?;lA was noted as judged by Kamofsky's criteria. 5 The 2 patients witlh locally extended infiltration without distant metastases before embolization survived for 18 to 35 of 26.5 months. Six ''"''""'°'""" .yrnp,ncic,rte responsiveness to ptty1:011eim11g1~lc1U:mn was 16 patients who underwent renal. cancer embolization, The response values were ± counts per minute in the presence of autologous serum and 21,379 ± 5,669 counts per minute in the presence of homologous serum before embolization 1). Statistically significant differences were noted rmnn,ar~·n to the controls (p <0.01 and <0.05, respecbut there was no significant difference in the response values between patients with and without distant metastases. The values 2 weeks after embolization decreased to a level of 14,437 ± 11,304 counts per minute in the presence of aucvJtu~,vut
----+------~------. . ---~---~---·< w. 1 m. 2 m, m. after embolizalion
after
Time a.Her treatmeni
B 50
~
~40 E
CL
u
Pre.
2w.
1m.
2m.
after embolization
1m.
2m.
~4m.
after nephrectomy
Time after treatrnent Fm. 1. Lymphocyte response to phytohemagglutinin (counts minute) in presence of autologous (A) and homologous (B) serum patients with renal cancer before and after transcatheter embolization of renal artery of tumorous kidney and after nephrectomy. Horizontat bars indicate mean percentage and vertical bars indicate ± 1 standard deviation. Shaded areas indicate normal range ± l standard deviation of 94 healthy volunteers.
ther to 25,546 ± 9,296 and 24,705 ± 5,875 counts per uuuuc•c, respectively, in the presence of homologous serum. However, there was no significant difference between values before and after embolization.
26
NAKANO, NIHIRA AND TOGE
80 C 0
-
;g 6
.c
•
C
0 1:40 QI
I:!
•
t
Cl/
a.
20
0
I •
Pre.
2 w. 1 rn. 2 rn. after embolization
1 rn. 2 rn. 2;4m. after nephrectorny
Time atter treatment FIG. 2. Percentage of inhibition of lymphocyte response to phytohemagglutinin by autologous serum from patients with renal cancer before and after transcatheter embolization of renal artery of tumorous kidney and after nephrectomy. Horizontal bars indicate mean and vertical bars indicate ± 1 standard deviation.
In contrast, in patients who underwent nephrectomy within 5 weeks after embolization the response values increased after nephrectomy in the presence of either autologous or homologous serum, and there was a significant difference only between the high value of 32,890 ± 12,070 counts per minute 2 months after nephrectomy and the values before embolization in the presence of autologous serum (p <0.05). Changes of serum inhibitory factor levels after embolization. The changes of serum inhibitory factor levels after renal cancer embolization were examined. The level before embolization was 20.6 ± 19.8 per cent and 2 weeks after embolization it was 43.4 ± 27.4 per cent, being higher in 5 of 6 patients examined but no significant increase was observed (fig. 2). The subsequent inhibitory rates were 27.6 ± 15.3 and 21.1 ± 15.4 per cent l and 2 months after embolization, respectively, with no difference between rates before and after embolization. On the contrary, in patients who underwent nephrectomy within 5 weeks after embolization the rate decreased remarkably, that is the inhibitory rate decreased to 18.2 ± 23. 7 per cent l month after nephrectomy, 5.9 ± 10.0 per cent 2 months after nephrectomy and 1.9 ± 4.3 per cent ~4 months after nephrectomy. There was a significant difference between the value 2 months postoperatively and that before embolization (p <0.05). Furthermore, inhibition oflymphocyte response by autologous sera was not observed in 4 of 5 patients for ~4 months after nephrectomy subsequent to embolization. Consequently, nephrectomy may cause a decrease in serum inhibitory factors. DISCUSSION
One of the causes responsible for spontaneous regression of primary and metastatic lesions in renal cancer is considered to be ischemia ascribable to circulatory disturbance in the tumor. Bloom reported ligation of a renal artery in a patient with renal cancer but no effect of the ligature on the metastatic lesions was observed. 1Obstruction ofrenal blood supply by this method seems inadequate because blood supply from collateral circulation and renal veins is considered to be present. Renal cancer embolization is considered to differ from ligation because it is possible to occlude the peripheral arteries under the control of that artery. Therefore, it was surmised that diffuse necrosis in the primary lesion leads to the regression of the metastatic lesions. 6 In regard to the clinical effects we have reported that embolization of renal cancer is efficacious as treatment before nephrectomy and also as conservative therapy in patients who cannot undergo nephrectomy from the therapeutic viewpoint of inhibition of the blood supply to the tumor. 2 From histolog-
ical findings of renal cancer resected after embolization it has been assumed that embolization is associated with necrosis of tumor tissue, promotion of lymphocyte infiltration and formation of fibrous membranes around the residual tumor tissue. 2 Generally, the inhibitory response to proliferative growth of cancer cells involves histologically proliferation of connective tissue of the interstitial cells and infiltration of various inflammatory cells in tumor tissue,7 and formation of fibrous membranes around the residual tumor cells. 8 It is said that the stronger the interstitial response the better the prognosis, especially since the lymphocyte infiltration represents the local defense mechanism and immunological pheQomenon. 7 In our study of patients with metastatic renal cancer combined embolization and nephrectomy enabled 2 of 5 patients (40 per cent) to survive ~2 years, while 4 of 7 (approximately 57 per cent) survived ~l years with embolization therapy only. These results accord a better prognosis than that reported previously. 9- 11 Our results are considered to be related to the presence of the aforementioned interstitial reaction. In this regard, Helmstein first devised hydrostatic pressure therapy for bladder tumors and elucidated the immunological mechanism between tumor tissues and tumor-bearing host. 12 Since infiltration of lymphocytes and plasma cells is a histological response to hydrostatic pressure therapy it has been suggested that this reaction participates in the immunological response. 12 There is evidence that specific immunological responses occur through the mediation of substances originating from the destroyed cells. 13 Our results and those of a previous study14 show that cell-mediated immunity in patients with renal cancer is lower than that of healthy subjects. However, there is little information about the immunological reaction after transcatheter arterial embolization in patients with renal cancer and the mechanism of the effects of this procedure still is unclear. It seems that the adverse effects of embolization on the immunological system are comparatively mild and occur only for extremely short intervals. It is likely that the patients are in a transient cachectic condition2 owing to unknown substances, such as massive toxic substances released temporarily into the circulation from the necrotic tissues of renal cancer, and that a part of the defect of the immunological response is caused by cachexia 15 and an increase of inhibitory factors in the serum. 3 In patients with renal cancer who underwent nephrectomy only cell-mediated immunity using the microtoxicity assay is reported to increase significantly compared to that of preoperative patients.16 However, the assay was done in the presence of homologous serum. In the presence of autologous serum the immunity after nephrectomy became lower than that of preoperative patients in most cases. It has been reported that the number of T cells after nephrectomy decreased transiently and did not increase significantly compared to that before nephrectomy during subsequent long-term observation. 17 However, in patients who underwent combined therapy with embolization and nephrectomy there was a significant increase in T cells 14 and also in the responsiveness to phytohemagglutinin in the presence of autologous serum in our study. Although the patients treated by palliative embolization were inoperable and in the terminal stage, and the period of immunotherapy was extremely short in most cases, lymphocyte responsiveness was maintained at the level before embolization or improved during long-term observation. Consequently, it seems that improved prognosis in our series paralleled improved immunity after embolization. High inhibitory factors are considered to be present in a 2 globulin 17 and immunoglobulin G 13 fractions. In our study the serum inhibitory factors were determined by calculation based on the difference in lymphocyte response value to phytohemagglutinin in patients with renal cancer when adding autologous serum and healthy serum. The patients with distant metastases had a significant increase in the inhibitory factor level before embolization than those without metastases. The increase in
TRANSCATHETER JEMBOLIZATION FOR RENAL CANCER
factors of autologous serum on lymphocyte responsiveness in who underwent renal cancer embolization may be assumed to have been affected by toxic substances from the tumor and entering the circulatory system necrotic tissues of the primary lesion. The """'""',."'" levels tended to be high for a certain interval after decreased significantly from 2 when nephrectomy was done within ~u«vovrn,-,.N,,,. This fact shows that an irre-
27
5. Karnofsky, D. A.: Meaningful clinical classification of therapeutic responses to anticancer drugs. Clin. Pharm. Ther., 2: 709, 1961. 6. Sophocles, A. M., Jr. and Nadler, S. H.: Immunologic aspects of cancer. Surg., Gynec. & Obst., 133: 321, 1971. 7. Enjoji, M.: Mesenchymal reaction in tumor-bearing host. In: Cancer Immunotherapy. Edited H. Kobayashi and T. Tachibana. Tokyo: Asakura Shoten, 2, p. 289, 1974. 8. Ohkita, K., Matsumura, Y., T. and Katayama, Y.: A statistical and pathological study on the tumors of the upper urinary tracts with some follow-up studies. Nishinihon J. UroL, 31: 343, 1969.
embolization and ntonh,re>l'i-,,mu the inhibitory factor serve as an index of an efficacy of '" h " " ~ " ' " estimation of the prognosis. In
REFERENCES 1. Bloom, H.J. G.: Hormone-induced and spontaneous regression of
metastatic renal cancer. Cancer, 32: 1066, 1973. Nakano, H.: Study on transcatheter embolization for renal carcinoma. 2nd Report-host immune rntm(m,,e after transcatheter embolization. J. Urnl., 71: 913, 3. Ikeda, Senoo, N., Niimoto, M. and Hattori, T.: Lvmrlhc,cvte responsiveness to phytohemagglutinin (FHA) and serum m1nb1tor, effect in patients with gastric cancer. Jap. J. Surg., 6: 157, 1976. 4. Wallace, D. M., Chisholm, G. D. and Hendry, W. F.: T.N.M. classification for urological tumours (U.I.C.C.)-1974. Brit. J. Urol.., 47: 1, 1975.
9. Skinner, D. G. and deKernion, J. B.: Clinical manifestations and treatment of renal parenchymal tumors. In: Genitourinary Can-· cer. Philadelphia: W. B. Saunders Co., cha.pt. 5, p. 107, 1978. 10. Katz, S. A. and Davis, J. E.: Renal adenocarcinoma: prognostics and treatment reflected by survival. Urology, HI: 10, 1977. 11. Middleton, R. G.: Surgery for metastatic renal cell carcinoma. J. Urol., !ll7: 973, 1967. 12. Helmstein, K.: Treatment of bladder carcinoma pressure technique. Report on 43 cases. Brit. J. 1972. 13. Bubenik, J., Perlmann, P., Helrnstein, K. and Moberger, G.: Cellular and humoral immune responses to human urina,y bladde,- c,a. cinomas. Int. J. Cancer, 5: 310, 1970. 14. Carmignani, G., Belgrano, E., Puppo, P. and Comaglia, P.: T and B
lymphocyte levels in :renal cancer patients: influence of preoperative transcatheter embolization and radical nephrectomy. ,J Urol., 118: 941, 1977. 15. Chabner, B. A., DeVita, V. T., Livingston, D. M. and Oliverio, V. T.: Abnormalities of tryptophan metabolism and doxal phosphate in Hodgkin's disease. New Engl. 838, 1970. 16. Montie, J. E., Straffon, R. A., Deodchar, S. D. and Barna, .El.. fo vitro assessment of cell-mediated immunity in patients with renal cell carcinoma. J. Urol., 115: 239, 1976. 17. Morales, A. and Eidinger, D.: Immune :reactivity in renal cancer: a sequential study. J. Urol., 115: 510, 1976.
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