THE JOURNAL OF UROLOGY
Vol. 113, .January
Copyright © 1975 by The Williams & Wilkirrn Co.
Printed in U.S.A.
CHEMOTHERAPY OF ADVANCED RENAL CELL CARCINOMA WITH VINBLASTINE AND CCNU C. MERRIN, A. MITTELMAN, N. FANOUS, Z. WAJSMAN
AND
G. P. MURPHY
From the Roswell Park Memorial Institute, New York State Department of Health and the State University, Buffalo, New York
viva! of tumor bearing animals were observed. 8 Vinblastine alone demonstrated a higher antitumor activity than CCNU or the combination. These findings encouraged us to test these drugs in man. Our results from an intensive 3-year trial are presented herein.
Generally. chemotherapy for carcinoma of the kidney bas heen disappointing. Recently, Talley and associates critically reviewed a variety of chemotherapeutic agents used in the treatment of this disease and documented their ineffectiveness.'· 2 Bloom and Wa))ace recommended the u~ of prcigestational agents OT audrageuic substances which have proved somewhat effective in the hamster. 3 • 4 In· man, this type of therapy h_as shown relatively modest results.' In recent times, no additional clinical progress has been achieved. However, there appears to be some effective drugs for the treatment of widespread renal cell carcinoma. 6 A new murine renal cell carcinoma was developed at Roswell Park Memorial Institute and served as a new experimental model. 7 This model exhibited some response to testing with viublastine or chloroethyl-cyclohexY.:-nitrosamea (CCNU). Both drugs are alkylating agents. Vinblastine has been used since the 1950s and it is known to inhibit mitosis. It also blocks the pathway of amino acids leading from glutamic acid to the purine synthesis, citric acid cycle and to urea. CCNU 1 has the dual capacity of alkylating deoxyribonucleic acid (DNA) with ribonucleic acid and possibly inactivating the enzymes necessary for the repair of the damaged DNA. These 2 drugs have been experimentally tested separately and in combination. 7 A decrease in tumor weight, the percentage of distant metastases and a significant prolongation in sur-
i,
METHODS
General. Forty-four patients were entered in the study between December 1971 and April 1974. All were referred for treatment by other urologists and surgeons. All patients had histologically proved renal cell carcinoma with widespread metastases. Patients ranged in age from 38 to 70 years, with an average of 59. All those studied had measurable radiological lesions of malignant disease. All individuals were followed up to the time of their death. The average time of followup was 8 months. Evaluation. The patients were evaluated by physical examination, excretory urography, renal angiography, venacavography, chest x-ray, tomography, metastatic bone survey, bone marrow aspiration, isotope scanning, and biochemical and hematological routine determinations. All patients had undergone operations for the removal of tne primary tumor._Jhe patients were d1v1ded mto--3 g ~ ) . In group 1, 5 patients had been treated with medroxyprogesterone acetate,* 3 received previous radiotherapy and 15 patients were not previously treated other than by operation. In group 2, comprising 6 patients, none had previous non-surgical treatment. In group 3, 3 patients had received previous radiotherapy, 2 had been on chemotherapy with mytomycin C and 10 were not previously treated. The interval between removal of the primary tumor and the beginning of the present chemotherapy in all groups varied from 1 to 8 months, with an average of 3 months. All patients had clinical progression of the disease as judged by the aforementioned tests. Twenty-three patients in group 1 received CCNU alone at a dose of 130 mg. per meter square every 6 weeks (table 2). Six patients in group 2 received CCNU and vinblastine and 15 patients in group 3 received methyl CCNU and vinblastine. The dose of vinblastine was 5 mg. per meter square every week for 7 weeks. The dose of methyl CCNU was the same as CCNU. Complete blood counts were obtained 2 times
Accepted for publication June 28, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. Supported in part by the United States Public Health Service Grants RR-05648-08 and RR-00262-09. 1 Talley, R. W., Moorhead, E. L., II, Tucker, W. G., San Diego, E. L. and Brennan, M. J.: Treatment of metastatic hypernephroma. J.A.M.A., 207: 322, 1969. 2 Talley, R. W.: Proceedings: chemotherapy of adenocarcinoma of the kidney. Cancer, 32: 1062, 1973. 3 Bloom, H.J. G.: Medroxyprogesterone acetate (provera) in the treatment of metastatic renal cancer. Brit. J. Cancer, 25: 250, 1971. • Bloom, H.J. and Wallace, D. M.: Hormones and the kidney, possible therapeutic role of testosterone in a patient with regression of metastases from renal adenocarcinoma. Brit. Med. J., 2: 476, 1964. 5 Wagle, D. G. and Murphy, G. P.: Hormonal therapy in advanced renal cell carcinoma. Cancer, 28: 318, 1971. 6 Mittelman, A., Albert, D. J. and Murphy, G. P.: Lomustine treatment of metastatic renal cell carcinoma. J.A.M.A., 225: 32, 1973. 7 Hrushesky, W. J. and Murphy, G. P.: Evaluation of chemotherapeutic agents in a new murine renal carcinoma model. J. Natl. Cancer Inst., 52: 1117, 1974.
8 Creasey, W. A., Bensch, K. G. and Malawista, S. E.: Colchicine, vinblastine and griseofulvin. Pharmacological studies with human leukocytes. Biochem. Pharmacol., 20: 1579, 1971. * Provera, The Upjohn Co., Kalamazoo, Michigan.
21
22
MERRIN AND ASSOCIATES
TABLE
L Distribution of patients into clinical groups for chemotherapy of advanced renal cell carcinoma, stage IV Pts. Previously Treated Group
TABLE
Medroxypro- Radiotherapy gesterone
Pts. Untreated
Total Pts.
Present Chemotherapy
CCNU CCNU, vinblastine Methyl CCNU, vinblastine
Others
5 0 0
3 0 3
0 0 2
15
23
2 3
6
6
10
15
Totals
5
6
2
31
44
2. Schedule of chemotherapy in advanced renal
cell carcinoma Groups
Drugs
Dose
1
CCNU
130 mg.Im 2/6 wks.
2
CCNU Vinblastine
130 mg.Im 2/6 wks. 5mg./m'/wk.
3
MethylCCNU Vinblastine
130 mg./m 2/6 wks. 5 mg./m 2/wk.
weekly after the first dose and then 1 time weekly. Routine biochemical evaluation was done biweekly. All patients were evaluated 3 and 6 weeks after the first dose. If hematologic depression (platelet count less than 100,000 and white count less than 4,000) persisted for 6 weeks after the drug administration, additional observation time was invoked until the bone marrow recovered and the white blood count was more than 4,000. When leukopenia reached a level of 1,000 or less, the patient was placed in reverse isolation and received adequate transfusion of white blood cells and platelets. A system was constructed in order to define the different degrees of response. Objective response was defined as 50 per cent decrease of a measurable lesion. Stabilization was defined as no change in size of lesions or symptoms, that is definite evidence of lack of disease progression. Subjective responses were also defined as decrease of pain and a general sensation of well being. RESULTS
In group 1, 3 patients received 1 dose of CCNU and were subsequently lost to followup or died before the next dose could be given (table 3). Four patients had an objective response lasting from 3 to 6 months. Two patients remained stable for 8 months and 14 patients showed uncontrollable progress of the disease. In group 2 we observed 1 objective response for 6 months. Three patients remained stable for 6 to 10 months and 2 patients had progression of the disease. In group 3 we observed 1 objective response for 4 months and 6 subjective responses with stabilization of the disease for up to 10 months. Two patients were lost to followup after the first dose and 6 patients did not respond to therapy. The CCNU therapy showed 20 per cent objective regression of the lesions and 10 per cent had symptomatic improvement with stabilization of
the disease, showing a total of 30 per cent response rate in group 1. On the other hand, patients treated with CCNU and vinblastine exhibited a 10 per cent objective response and a 50 per cent symptomatic improvement with arrest of disease progress for up to 10 months. Thus, a total of 60 per cent responses were noted in group 2. Methyl CCNU and vinblastine resulted in 7.6 per cent objective responses and 46.6 per cent stabilization of the disease for up to 11 months, for a total response in group 3 of 54.2 per cent. DISCUSSION
Our study indicates significant therapeutic effects when compared to any chemotherapeutic agent available until now. The most effective of them, medroxyprogesterone acetate, produced only 11.4 per cent objective response in a recent series of 61 patients treated by Talley. 2 Our objective response with the single agent CCNU is considerably higher than this response rate. In addition, the combination of vinblastine and CCNU proved comparable to other studies. 5 The subjective response in our study varies from 10 per cent with CCNU to 50 per cent with combination CCNU and vinblastine. The over-all response (subjective and objective) seems to be superior to hormonal agents used to date. 1 · 2 We mus!_also carefully consider the fact that all patients in the present study were prev10us clinical failures (§!age IV) with advanced and progressive disease. Some represented a failure of thernpy with hormonal agents, with radiation or with other chemotherapy. The ro nosis of such a group of patients at best is less than 6 months. 9 On t is asis t e resu ts- of this clinical study are most striking. Doubtle~, similar chemotherapy of patients with better st.M"_e oCflieirtumor as well as earlier m the course of tg_eir disease will prove to be a beneficial program on the basis af the cmreut results. The sex, age and distribution of metastases did not detectably influence the therapeutic response. '.J:he single age~ CCNU alone seems to b ~ e effective than the combination CCNU and vinblast!lli!.:_ 'l'fj1s fact might be explamed by some compEtljtive inhibitory action of both agents given together on the reproductive cycle of the tumor 9 Varkarakis, M. J ., Bhanalaph, T., Moore, R. H. and Murphy, G. P.: Prognostic criteria of renal cell carcinoma. J. Surg. Oncol., 6: 97, 1974.
CHEMOTHERAPY OF ADV AN CED RENAL CELL CARCINOMA TABLE
3. Ubjective and subjective responses obtained following chemotherapy of advanced renal cell carcinoma. Group
1-CCNU 2-CCNU, vinblastine 3-Metbyl CCNU
Lost lo Followup or Early Death
Objective Response No.(%)
;3
4 (20) 1 (16) 1 (7.6)
0
2
Stable Subjective Response No.(%) 2 (10) 3 (50) 6 (46.6)
cell. However, prior treatment may have affected cellular kinetics and clinical response. In our study we did not choose to try vinblastine alone because previous clinical trials by other investigators reported minimal effects. 1- 11 CCNU represents a limited but significant progress in the treatment of metastatic renal cell carcinoma. Its use should be recommended in earlier stages of the disease when its effectiveness 10 Murphy, G. P. and Hrushesky, W ..J.: A murine renal cell carcinoma. J. Natl. Cancer Inst., 50: 101:l, 1973. 11 Brockman. R. W.: Biochemical aspects of drug combination. Can. Chema. Reports,. part 2, 52: 115, 1974.
No Effects J\o. (Sc) 14 (70)
2 (:38) 6 (45.8)
Total Response No.(%)
Total Pts.
6 (30)
23
4 (66) 7 (,S4.2)
G 15
is potentially higher. Further evaluation investigators is recommended.
otl-ier
SCMMARY
Forty-four patients with advanced renal cell carcinoma (stage IV) were divided into :3 groups. The 2:3 patients in group 1 received CCNU alom,, the 6 patients in group 2 received CC;\;U and vinblastine and the 15 patients in group ;3 received methyl CCNU and vinhlastine. The over-all re sponse. subjective and objective, was :30 per cent in group 1, 60 per cent in group :2 and 54 per cent in group 3. These results are compared to other existing modalities of treatment and appear to be superior.
Vol. 113, .January
Copyright © 1975 by The Williams & Wilkirrn Co.
Printed in U.S.A.
CHEMOTHERAPY OF ADVANCED RENAL CELL CARCINOMA WITH VINBLASTINE AND CCNU C. MERRIN, A. MITTELMAN, N. FANOUS, Z. WAJSMAN
AND
G. P. MURPHY
From the Roswell Park Memorial Institute, New York State Department of Health and the State University, Buffalo, New York
viva! of tumor bearing animals were observed. 8 Vinblastine alone demonstrated a higher antitumor activity than CCNU or the combination. These findings encouraged us to test these drugs in man. Our results from an intensive 3-year trial are presented herein.
Generally. chemotherapy for carcinoma of the kidney bas heen disappointing. Recently, Talley and associates critically reviewed a variety of chemotherapeutic agents used in the treatment of this disease and documented their ineffectiveness.'· 2 Bloom and Wa))ace recommended the u~ of prcigestational agents OT audrageuic substances which have proved somewhat effective in the hamster. 3 • 4 In· man, this type of therapy h_as shown relatively modest results.' In recent times, no additional clinical progress has been achieved. However, there appears to be some effective drugs for the treatment of widespread renal cell carcinoma. 6 A new murine renal cell carcinoma was developed at Roswell Park Memorial Institute and served as a new experimental model. 7 This model exhibited some response to testing with viublastine or chloroethyl-cyclohexY.:-nitrosamea (CCNU). Both drugs are alkylating agents. Vinblastine has been used since the 1950s and it is known to inhibit mitosis. It also blocks the pathway of amino acids leading from glutamic acid to the purine synthesis, citric acid cycle and to urea. CCNU 1 has the dual capacity of alkylating deoxyribonucleic acid (DNA) with ribonucleic acid and possibly inactivating the enzymes necessary for the repair of the damaged DNA. These 2 drugs have been experimentally tested separately and in combination. 7 A decrease in tumor weight, the percentage of distant metastases and a significant prolongation in sur-
i,
METHODS
General. Forty-four patients were entered in the study between December 1971 and April 1974. All were referred for treatment by other urologists and surgeons. All patients had histologically proved renal cell carcinoma with widespread metastases. Patients ranged in age from 38 to 70 years, with an average of 59. All those studied had measurable radiological lesions of malignant disease. All individuals were followed up to the time of their death. The average time of followup was 8 months. Evaluation. The patients were evaluated by physical examination, excretory urography, renal angiography, venacavography, chest x-ray, tomography, metastatic bone survey, bone marrow aspiration, isotope scanning, and biochemical and hematological routine determinations. All patients had undergone operations for the removal of tne primary tumor._Jhe patients were d1v1ded mto--3 g ~ ) . In group 1, 5 patients had been treated with medroxyprogesterone acetate,* 3 received previous radiotherapy and 15 patients were not previously treated other than by operation. In group 2, comprising 6 patients, none had previous non-surgical treatment. In group 3, 3 patients had received previous radiotherapy, 2 had been on chemotherapy with mytomycin C and 10 were not previously treated. The interval between removal of the primary tumor and the beginning of the present chemotherapy in all groups varied from 1 to 8 months, with an average of 3 months. All patients had clinical progression of the disease as judged by the aforementioned tests. Twenty-three patients in group 1 received CCNU alone at a dose of 130 mg. per meter square every 6 weeks (table 2). Six patients in group 2 received CCNU and vinblastine and 15 patients in group 3 received methyl CCNU and vinblastine. The dose of vinblastine was 5 mg. per meter square every week for 7 weeks. The dose of methyl CCNU was the same as CCNU. Complete blood counts were obtained 2 times
Accepted for publication June 28, 1974. Read at annual meeting of American Urological Association, St. Louis, Missouri, May 19-23, 1974. Supported in part by the United States Public Health Service Grants RR-05648-08 and RR-00262-09. 1 Talley, R. W., Moorhead, E. L., II, Tucker, W. G., San Diego, E. L. and Brennan, M. J.: Treatment of metastatic hypernephroma. J.A.M.A., 207: 322, 1969. 2 Talley, R. W.: Proceedings: chemotherapy of adenocarcinoma of the kidney. Cancer, 32: 1062, 1973. 3 Bloom, H.J. G.: Medroxyprogesterone acetate (provera) in the treatment of metastatic renal cancer. Brit. J. Cancer, 25: 250, 1971. • Bloom, H.J. and Wallace, D. M.: Hormones and the kidney, possible therapeutic role of testosterone in a patient with regression of metastases from renal adenocarcinoma. Brit. Med. J., 2: 476, 1964. 5 Wagle, D. G. and Murphy, G. P.: Hormonal therapy in advanced renal cell carcinoma. Cancer, 28: 318, 1971. 6 Mittelman, A., Albert, D. J. and Murphy, G. P.: Lomustine treatment of metastatic renal cell carcinoma. J.A.M.A., 225: 32, 1973. 7 Hrushesky, W. J. and Murphy, G. P.: Evaluation of chemotherapeutic agents in a new murine renal carcinoma model. J. Natl. Cancer Inst., 52: 1117, 1974.
8 Creasey, W. A., Bensch, K. G. and Malawista, S. E.: Colchicine, vinblastine and griseofulvin. Pharmacological studies with human leukocytes. Biochem. Pharmacol., 20: 1579, 1971. * Provera, The Upjohn Co., Kalamazoo, Michigan.
21
22
MERRIN AND ASSOCIATES
TABLE
L Distribution of patients into clinical groups for chemotherapy of advanced renal cell carcinoma, stage IV Pts. Previously Treated Group
TABLE
Medroxypro- Radiotherapy gesterone
Pts. Untreated
Total Pts.
Present Chemotherapy
CCNU CCNU, vinblastine Methyl CCNU, vinblastine
Others
5 0 0
3 0 3
0 0 2
15
23
2 3
6
6
10
15
Totals
5
6
2
31
44
2. Schedule of chemotherapy in advanced renal
cell carcinoma Groups
Drugs
Dose
1
CCNU
130 mg.Im 2/6 wks.
2
CCNU Vinblastine
130 mg.Im 2/6 wks. 5mg./m'/wk.
3
MethylCCNU Vinblastine
130 mg./m 2/6 wks. 5 mg./m 2/wk.
weekly after the first dose and then 1 time weekly. Routine biochemical evaluation was done biweekly. All patients were evaluated 3 and 6 weeks after the first dose. If hematologic depression (platelet count less than 100,000 and white count less than 4,000) persisted for 6 weeks after the drug administration, additional observation time was invoked until the bone marrow recovered and the white blood count was more than 4,000. When leukopenia reached a level of 1,000 or less, the patient was placed in reverse isolation and received adequate transfusion of white blood cells and platelets. A system was constructed in order to define the different degrees of response. Objective response was defined as 50 per cent decrease of a measurable lesion. Stabilization was defined as no change in size of lesions or symptoms, that is definite evidence of lack of disease progression. Subjective responses were also defined as decrease of pain and a general sensation of well being. RESULTS
In group 1, 3 patients received 1 dose of CCNU and were subsequently lost to followup or died before the next dose could be given (table 3). Four patients had an objective response lasting from 3 to 6 months. Two patients remained stable for 8 months and 14 patients showed uncontrollable progress of the disease. In group 2 we observed 1 objective response for 6 months. Three patients remained stable for 6 to 10 months and 2 patients had progression of the disease. In group 3 we observed 1 objective response for 4 months and 6 subjective responses with stabilization of the disease for up to 10 months. Two patients were lost to followup after the first dose and 6 patients did not respond to therapy. The CCNU therapy showed 20 per cent objective regression of the lesions and 10 per cent had symptomatic improvement with stabilization of
the disease, showing a total of 30 per cent response rate in group 1. On the other hand, patients treated with CCNU and vinblastine exhibited a 10 per cent objective response and a 50 per cent symptomatic improvement with arrest of disease progress for up to 10 months. Thus, a total of 60 per cent responses were noted in group 2. Methyl CCNU and vinblastine resulted in 7.6 per cent objective responses and 46.6 per cent stabilization of the disease for up to 11 months, for a total response in group 3 of 54.2 per cent. DISCUSSION
Our study indicates significant therapeutic effects when compared to any chemotherapeutic agent available until now. The most effective of them, medroxyprogesterone acetate, produced only 11.4 per cent objective response in a recent series of 61 patients treated by Talley. 2 Our objective response with the single agent CCNU is considerably higher than this response rate. In addition, the combination of vinblastine and CCNU proved comparable to other studies. 5 The subjective response in our study varies from 10 per cent with CCNU to 50 per cent with combination CCNU and vinblastine. The over-all response (subjective and objective) seems to be superior to hormonal agents used to date. 1 · 2 We mus!_also carefully consider the fact that all patients in the present study were prev10us clinical failures (§!age IV) with advanced and progressive disease. Some represented a failure of thernpy with hormonal agents, with radiation or with other chemotherapy. The ro nosis of such a group of patients at best is less than 6 months. 9 On t is asis t e resu ts- of this clinical study are most striking. Doubtle~, similar chemotherapy of patients with better st.M"_e oCflieirtumor as well as earlier m the course of tg_eir disease will prove to be a beneficial program on the basis af the cmreut results. The sex, age and distribution of metastases did not detectably influence the therapeutic response. '.J:he single age~ CCNU alone seems to b ~ e effective than the combination CCNU and vinblast!lli!.:_ 'l'fj1s fact might be explamed by some compEtljtive inhibitory action of both agents given together on the reproductive cycle of the tumor 9 Varkarakis, M. J ., Bhanalaph, T., Moore, R. H. and Murphy, G. P.: Prognostic criteria of renal cell carcinoma. J. Surg. Oncol., 6: 97, 1974.
CHEMOTHERAPY OF ADV AN CED RENAL CELL CARCINOMA TABLE
3. Ubjective and subjective responses obtained following chemotherapy of advanced renal cell carcinoma. Group
1-CCNU 2-CCNU, vinblastine 3-Metbyl CCNU
Lost lo Followup or Early Death
Objective Response No.(%)
;3
4 (20) 1 (16) 1 (7.6)
0
2
Stable Subjective Response No.(%) 2 (10) 3 (50) 6 (46.6)
cell. However, prior treatment may have affected cellular kinetics and clinical response. In our study we did not choose to try vinblastine alone because previous clinical trials by other investigators reported minimal effects. 1- 11 CCNU represents a limited but significant progress in the treatment of metastatic renal cell carcinoma. Its use should be recommended in earlier stages of the disease when its effectiveness 10 Murphy, G. P. and Hrushesky, W ..J.: A murine renal cell carcinoma. J. Natl. Cancer Inst., 50: 101:l, 1973. 11 Brockman. R. W.: Biochemical aspects of drug combination. Can. Chema. Reports,. part 2, 52: 115, 1974.
No Effects J\o. (Sc) 14 (70)
2 (:38) 6 (45.8)
Total Response No.(%)
Total Pts.
6 (30)
23
4 (66) 7 (,S4.2)
G 15
is potentially higher. Further evaluation investigators is recommended.
otl-ier
SCMMARY
Forty-four patients with advanced renal cell carcinoma (stage IV) were divided into :3 groups. The 2:3 patients in group 1 received CCNU alom,, the 6 patients in group 2 received CC;\;U and vinblastine and the 15 patients in group ;3 received methyl CCNU and vinhlastine. The over-all re sponse. subjective and objective, was :30 per cent in group 1, 60 per cent in group :2 and 54 per cent in group 3. These results are compared to other existing modalities of treatment and appear to be superior.
