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Intravesical Recombinant Tumor Necrosis Factor in the Treatment of Superficial Bladder Cancer: An Eastern Cooperative Oncology Group Study
0022-5347/95/1541-0066$03.00/0
Vol. 154,66-68,July 1995 Printed i n U . S . A
T H E JOURh'AL OF UROl,OGY
Copynght 0 1995 by
AMERICAN
UROLOGICAL ASSOC'LATION, INC.
INTRAVESICAL RECOMBINANT TUMOR NECROSIS FACTOR IN THE TREATMENT OF SUPERFICIAL BLADDER CANCER: AN EASTERN COOPERATIVE ONCOLOGY GROUP STUDY DAVID B. GLAZIER, ROBERT R. BAHNSON, DAVID G. McLEOD, REINHARD W. EDWARD M. MESSING AND MARC S. ERNSTOFF*
VON
ROEMELING,
From the Departments of Surgery (Section of Urology) and Medicine (Section of Hematology 1 Oncology), Norris Cotton Cancer Center, Lebanon, New Hampshire; Department of Urological Surgery, University of Pittsburgh School of Medicine, Pittsburgh and Department of Clinical Research (Section of Oncology), Sterling Winthrop Inc., Collegeuille, Pennsylvania; Division of Urology, Walter Reed Army Medical Center, Washington, D. C., and University of Wisconsin Medical School, Madison, Wisconsin
ABSTRACT
We tested and proved the safety of recombinant human tumor necrosis factor given intravesically weekly for 11 weeks (dwell time 2 hours) for the treatment of superficial bladder cancer in 8 men and 1woman 46 to 87 years old (mean age 69 years). Cohorts of 3 patients received 200, 400 and 1,000 pg. recombinant human tumor necrosis factor. The maximal tolerated dose was not achieved. There were 9 episodes of urological symptoms, 8 of flu-like symptoms, 4 of headache and 3 of chest tightness. Hematological and gastrointestinal toxicities were minor, and no renal toxicity was encountered. Recombinant human tumor necrosis factor was safe to administer a t doses up to 1,000 pg. We hope that recombinant human tumor necrosis factor in conjunction with other antitumor agents will lead to a new, effective treatment for superficial bladder cancer. KEY WORDS:bladder neoplasms, tumor necrosis factor
necrosis factor, which may be a mechanism of action of BCG antitumor activity in superficial bladder cancer. We assess the safety of recombinant h u m a n tumor necrosis have bladder cancer1 and at least 10,000 will die of metastatic disease. Superficial bladder cancer has been treated factor instilled into the bladder, and determine the degree of with a variety of techniques, including transurethral resec- local and systemic toxicity. We were prompted to conduct this tion, fulguration and intravesical chemotherapy or immuno- study i n view of previous animal studies,",'" particularly on therapy.2.3 More than half of the patients who present with cynomolgus monkeys in which doses of recombinant human bladder cancer have superficial disease, with pathological tumor necrosis factor (10 ng. to 1 mg.) were instilled intraevaluation showing equal distribution among grades 1 to 3. vesically and no observable toxicity from treatment was demPatients who have a complete response to transurethral re- onstrated. section andlor fulguration plus intravesical therapy have MATERIAL AND M E T H O D S shown a decreased risk for subsequent invasion or spread. Bacillus Calmette-Guerin (BCG), a n intravesical agent, apPatients who were enrolled in t h e study had to fulfill pears to decrease the recurrence rate of superficial bladder certain criteria. All patients had histologically confirmed cancer. The complete response rate has been reported to be as transitional cell carcinoma, stages 0 or I (Tis, Ta, Tl),and at high as 70%.4.5 The mechanism of action of this biological least 1 of several conditions: greater t h a n 2 recurrences in 1 response modifier is unclear. year, recurrence at 6 months or less after transurethral reIn prospective, randomized trials BCG has been demon- section of bladder tumor, 3 or more lesions present at diagstrated to be superior to other intravesical agents in prevent- nosis, or carcinoma i n situ. All patients had a n Eastern ing recurrence, and treating residual papillary tumors and Cooperative Oncology Group performance status of 0, 1 or 2 carcinoma in situ.6 The optimal BCG dosing schedule, effec- a t most, and all had adequate hematological, renal, coagulative toxicity management and administration strategies have tive and hepatic functions, a s well as a bladder capacity yet to be elucidated. Although the most frequent toxicities of greater than 60 ml. and ability to retain the urine for 2 hours. BCG intravesical therapy are transient, a certain group of Patients may have received prior chemotherapy, immunopatients will have local symptoms, such as bladder pain, too therapy or radiotherapy provided t h a t a t least 2 weeks had severe to continue treatment. Serious complications are rare elapsed from any prior therapy but they must have received but a fatal outcome has been reported.7 intravesical chemotherapy. Tumor necrosis factor was first described by Carswell e t al Patients with urinary extravasation on excretory urograa s a factor isolated from sera of endotoxin treated mice, phy were excluded, a s were those with a history of congestive sensitized previously with BCG.RThe antineoplastic action of heart failure, myocardial infarction within the last 6 months, tumor necrosis factor was confirmed when hemorrhagic ne- a diagnosis of New York Heart Association class 111 or uncrosis of tumor grafts in mice treated with tumor necrosis controlled arrhythmia. Patients were ineligible if they had factor was reported." BCG has been shown to induce tumor significant pulmonary disease, deep venous thrombosis, pulmonary embolus within l year, intermittent claudication, human immunodeficiency virus infection or a known seizure Accepted for publication December 2. 1994. Sup rted in part by National Cancer Institute Investigator disorder, or if they were pregnant or lactating. All patients A w a r r K 0 8 CA 01490 and National Cancer Institute Grants signed a written informed consent. The study chairman CA21115. CA23318, CA31076, CA06594 and CA18653. * Requests for reprints: Section of Hematology/Oncology, Dart- (M. S . E.) was notified before determining eligihility, reverimouth-Hitchcock Medical Center, One Medical Center Drive, Leha- fication and obtaining informed consent. Only after entry non, New Hampshire 03756-0001. onto the working list was the patient evaluated for study. Bladder cancer is the sixth leading cause of cancer death in the United States. In 1994, 51,200 people are expected to
66
67
RECOMBINANT TUMOR NECROSIS FACTOR I N TREATMENT OF BLADDER CANCER TABLE 1. Demoeraohics U
Dose Tier(wz.)
*
No.-Mean
No. Men/ No.Women
.
Tumor Grade
Prior Therapy
Performance Status*
Radiotherapy
'
200
3
0
2
1
0
3
0
400 1,000
3 1
1
0 1
1 1
2 1
3 2
0 1
Chemotherapy
3-69 2/1 3 3-68 310 3 3-7 1 310 3 Eastern Cooperative Oncology Group performance status.
Drug treatment. The recombinant human tumor necrosis factor was supplied through the Cancer Treatment Evaluation Program of the National Cancer Institute, and was administered weekly for I1 weeks in 50 cc of 0.9% (normal) saline with human serum albumin at 2 mg./ml. (100mg.150 ml.). The solution was infused by gravity flow into the bladder through a urinary catheter and was retained in the bladder for 2 hours before emptying. Following completion of the instillations, patients were monitored with cystoscopy and urinary cytology studies every 3 months. An excretory urogram was performed every year. Recurrence was diagnosed by visible tumor on cystoscopy, positive cytology study or bladder biopsy. RESULTS
The 8 men and 1woman studied (mean age 69 years, range 46 to 87) had been treated previously for superficial bladder cancer with transurethral resection of bladder tumors (9),
0
Instillations/
Pt.
Immunetherapy
RS.
'
1 11.11and 11 11, 1 1 a n d 9 4, 11 and 11
TABLE 2. Overall toxicities Dose Tier (crg.) 200
400
LOO0
Flu-like symptoms Headache Liver function tests* Hemet Respiratory tract infection Nausea Vomiting Diarrhea Pelvic pain Chest pain Cystitis Dysuria Bladder pain Urethritis Frequency
2 (1)
-
-
1(2) l(1) l(1)
l(1)
-
l(1) chemotherapy (9) and radiotherapy (1).No patient had rel(2) sidual tumors at initiation of intravesical therapy. Patients Values are given 88 toxicity grade (numberof patients). in each dose cohort were of excellent Eastern Cooperative * Altered liver function tests, grade 1.2.5 or less x Y CY = upper limit of Oncology Group status and similar mean age. The prepon- normal). derance of male patients reflects the distribution of the dist Altered hematological indexes, white blood cell value grade 1, 3.0 to 3.91 ease between the sexes. Table 1 shows the demographic 111111.3. makeup of the population. The overall toxicity and frequency of these events according to the National Institutes of Health common toxicity scores, as well as the urological toxicities TABLE3. Followup after transurethml resection of bladder tumor encountered are shown in table 2. In 5 of 9 patients mild and recombinant human tumor necrosis factor treatment urological symptoms occurred that could be related to cathNo. pta. (toxicity grade) eterization andor recombinant human tumor necrosis factor. Dose Tier No. pts. (M.) No Evidence of Regressive Also, mild flu-like symptoms were reported in 5 of the 9 Disease Disease patients and these occurred at all dose levels, suggesting a 200 systemic effect of intravesical recombinant human tumor 400 necrosis factor. Hematological and gastrointestinal toxicities LOO0 were minor, and no renal toxicity was encountered. The trial was discontinued at a 1,000 pg. recombinant human tumor necrosis factor dose tier, which was believed not to exceed clinical relevant dosages. Table 3 outlines patient response at remain tumor-free at 3 years and 90%with recurrent disease followup aRer transurethral resection of bladder tumors and at 3 months will continue to have recurrences for 3 years.13 recombinant human tumor necrosis factor treatment. BCG, thiotepa, mitomycin C and doxorubicin are some of One patient withdrew from the study after only 4 instilla- the more common agents used for intravesical therapy that tions and relapse was noted at followup cystoscopy. A total of have resulted in a decrease in recurrence rates.14-17 Inter8 patients had a complete response after transurethral re- feron in the prophylactic treatment of bladder cancer has section of bladder tumors and tumor necrosis factor treat- been shown to be less effective than mitomycin but it is better ment but all had relapse at a mean of 16 months (range 7 to tolerated.18 When used prophylactically, BCG has been 35). shown to be the most effective agent in preventing recurrences when coupled with transurethral resection of bladder DISCUSSION tumors, with cure rates of approximately 70%.16.19 The mechThe majority (75 to 85%) of bladder cancers are superficial anism of action of BCG is not fully understood. It has been in nature." Treatment is focused on 3 distinct goals, that is postulated that BCG may act by local imtation or through a to eliminate existing disease, prevent recurrence of tumor vaccination-type response. It is known that cytokine release and impede progression to muscle invasion or metastasis. has been associated with BCG therapy. Recombinant human The gold standard for initial treatment of superficial cancer tumor necrosis factor is a cytokine induced by BCG therapy. Tumor necrosis factor is a naturally occurring product is transurethral resection of bladder tumors. Heney et al reported that stage T1 tumors recurred in 70%of the patients known to stimulate natural killer and lymphokine-activated after 3 years and stage Ta tumors recurred in 55%.12 These killer cells, as well as to modulate granulocytes and Bcell recurrences are treated with transurethral resection of blad- function. Tumor necrosis factor is an antitumor agent that der tumors. Of patients with stage Ta, grade 1tumor who do has been shown in vitro to be cytotoxic and cytostatic, and it not have a cystoscopic recurrence at 3 months, 80% will appears to inhibit cell proliferation during the G2 phase of
68
RECOMBINANT TUMOR NECROSIS FACTOR IN TREATMENT OF BLADDER CANCER
the cell cycle.20 It has been suggested, based on mouse studies in which recombinant human tumor necrosis factor was associated with hemorrhagic necrosis of tumors, that tumor necrosis factor mediates endotoxin-induced tumor necrosis and may be linked to the suppression of transformed cells by activated macrophages.8 Bahnson and Ratliff confirmed that recombinant human tumor necrosis factor in conjunction with doxorubicin has antitumor activity in the mouse bladder tumor model in vitm but was ineffective in decreasing implantation of intravesical tumors in vivo.*o The wide varieties of toxicities reported with the systemic use of recombinant human tumor necrosis factor have not been confirmed in our intravesical studies. The maximum tolerated dose was not achieved. Further study of recombinant human tumor necrosis factor may be necessary, since the issue regarding the safety and toxicity spectrum of recombinant human tumor necrosis factor as a single agent when used intravesically has been determined. Given the interactions between tumor necrosis factor and chemotherapy agents, most noticeably mitomycin C and doxorubicin, a rational approach would be to combine these agents for intravesical use. Another rational approach is to combine tumor necrosis factor with other biological agents, specifically BCG or interferon-&.We have no evidence of efficacy for intravesical recombinant human tumor necrosis factor in the treatment of superficial bladder cancer and a larger phase I1 study should be performed, following which rational drug development can proceed. REFERENCES
1. Boring, C. C., Squires, T. S., Tong, T. and Montgomery, S.: Cancer statistics. CA, 44:7, 1994. 2. Soloway, M. S.: Rationale for intensive intravesical chemotherapy for superficial bladder cancer. J. Urol., 123: 461,1980. 3. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116 180, 1976. 4. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and as&ated immune responses. Cancer, 48.82, 1981. 5. Pinsky, C., Camacho, F., Kerr, D., Herr, H., Geller, N., Whitemore, W. and Ottegen, H.: Treatment of specified bladder cancer with intravesical BCG. Proc. Amer. Soc. Clin. Oncol., 2 57, 1983. 6. Guinan, P., Richardson, C., Hanna, M. and Rubenstein, M.: BCG in the management of superficial bladder cancer. Prog. Clin. Biol. Res., so9: 447, 1989. 7. Rawls, W. H., Lamm, D. L., Lowe, B. A., Crawford, E. D., Sarosdy, M. F., Montie, J. E., Grossman, H. B. and Scardino, P. T.: Fatal sepsis following intravesical bacillus CalmetteGuerin administration for bladder cancer. J. Urol., 144: 1328, 1990. 8. Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N. and Williamson, B.: An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl. Acad. Sci., 7 2 3666, 1975. 9. Bahnson, R. R., Ballou, B. T., Emstoff, M. S., Cramer, D. V., Schwentker, F. N., Reiland, J. M. and Hakala, T. R.: Toxicity of intravesical recombinant human tumor necrosis factor in cynomolgus monkeys. J. Biol. Resp. Mod., 9: 445, 1990. 10. Bahnson, R. R. and Ratliff, T. L.: In vitro and in vivo anti-tumor
activity of recombinant mouse tumor necrosis factor (TNF) in a mouse bladder tumor (MBT-2). J. Urol., 144: 172, 1990. 11. Herr, H. W., Laudone, V. P. and Whitmore, W. F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol., 138 1363, 1987. 12. Heney, N. M.. Ahmed, S., Flanagan, M. J., Frable, W.,Corder, M. P., Hafermann, M. D. and Hawkins, I. R. for National Bladder Cancer Collaborative Group A Superficial bladder cancer: progression and recurrence. J. Urol., 130 1083, 1983. 13. Fitzpatrick, J. M., West, A. B., Butler, M. R., Lane, V. and OFlynn, J. D.: Superficial bladder tumors (stage pTa. grades 1 and 2): the importance of recurrence pattern following initial resection. J. Urol., 135: 920, 1986. 14. Koontz, W. W., Jr., Prout, G. R., Smith, W., Frable, W. J. and Minnis, J. E.: The use of intravesical thio-tepa in the management of non-invasive carcinoma of the bladder. J. Urol., 12& 307, 1981. 15. Martinez-Piiieiro, J. A.: BCG vaccine in superficial bladder tumors: eight years later. Eur. Urol., 1 0 93. 1984. 16. Lamm, D. L., Crissinam, J., Blumenstein, B. A,, Crawford, E. D., Montie, J., Scardino, P., Grossman, H. B., Stanisic, T., Smith, J., Sullivan, J. and Sarosdy, M.: Adriamycin vs. BCG in superficial bladder cancer. A Southwest Oncology Group Study. In: BCG in Superficial Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meivden. New York: Alan R. Liss. Inc., pp. 263-270, 1989. 17. Irwin, R.. Zincke, H., Droller, M. J., Prout. G. R.. Jr. and Soloway, M. S.: Treatment modalities in superficial bladder cancer. Sem. Urol., suppl., 7: 1, 1989. 18. Boeeardo, F., Cannata, D., Rubagotti, A., Guameri, D., Decensi, A., Canobbio, L., Curotto, A,, Martorana, G., Pegoraro, C., Silvaggi, F., Salvia, G., Comeri, G., Bono, A., Borella, T. and Giuliani, L.: Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. J. Clin. Oncol., 12 7, 1994. 19. Herr, H. W.: Intravesical therapy. Hematol. Oncol. Clin. N. h e r . , 6: 117, 1992. 20. Darzynkiewicz, Z., Williamson, B., Carswell. E. A. and Old, L. J.: Cell cycle-specific effects of tumor necrosis factor. Cancer Res., 44 83, 1984. ~~~
EDITORIAL COMMENT
This phase I protocol seeks to optimize the dose and establish toxicities for the cytokine recombinant human tumor necrosis factor. Phase I clinical trials in superficial bladder cancer are unusual and require that patients entered have exhausted standard immunotherapeutic as well as chemotherapeutic regimens, and have a marker lesion in the bladder. This marker lesion is used to evaluate antineoplastic activity of the agent being evaluated in phases I and II clinical trials. In this trial a 1,000 pg. dose of this biological response modifier was well tolerated. As with many of the biological agents used in the treatment of superficial bladder cancer, the limiting dose is frequently dictated by the cost of the agent. Large doses of interferon exceeding 100 million IU can be administered with little to no toxicity. This clinical trial, as well as one that we have completed, establish the safety and, to some degree, the anti-cancer activity of the drug. Further clinical trials should proceed with this agent, perhaps combining it with other biological agents, alternating therapy with established chemotherapeutic drugs or as a single agent comparing it ta BCG or mitomycin C.
E. David Crawford Division of Urology University of Colorado Denver, Colorado
Vol. 154,66-68,July 1995 Printed i n U . S . A
T H E JOURh'AL OF UROl,OGY
Copynght 0 1995 by
AMERICAN
UROLOGICAL ASSOC'LATION, INC.
INTRAVESICAL RECOMBINANT TUMOR NECROSIS FACTOR IN THE TREATMENT OF SUPERFICIAL BLADDER CANCER: AN EASTERN COOPERATIVE ONCOLOGY GROUP STUDY DAVID B. GLAZIER, ROBERT R. BAHNSON, DAVID G. McLEOD, REINHARD W. EDWARD M. MESSING AND MARC S. ERNSTOFF*
VON
ROEMELING,
From the Departments of Surgery (Section of Urology) and Medicine (Section of Hematology 1 Oncology), Norris Cotton Cancer Center, Lebanon, New Hampshire; Department of Urological Surgery, University of Pittsburgh School of Medicine, Pittsburgh and Department of Clinical Research (Section of Oncology), Sterling Winthrop Inc., Collegeuille, Pennsylvania; Division of Urology, Walter Reed Army Medical Center, Washington, D. C., and University of Wisconsin Medical School, Madison, Wisconsin
ABSTRACT
We tested and proved the safety of recombinant human tumor necrosis factor given intravesically weekly for 11 weeks (dwell time 2 hours) for the treatment of superficial bladder cancer in 8 men and 1woman 46 to 87 years old (mean age 69 years). Cohorts of 3 patients received 200, 400 and 1,000 pg. recombinant human tumor necrosis factor. The maximal tolerated dose was not achieved. There were 9 episodes of urological symptoms, 8 of flu-like symptoms, 4 of headache and 3 of chest tightness. Hematological and gastrointestinal toxicities were minor, and no renal toxicity was encountered. Recombinant human tumor necrosis factor was safe to administer a t doses up to 1,000 pg. We hope that recombinant human tumor necrosis factor in conjunction with other antitumor agents will lead to a new, effective treatment for superficial bladder cancer. KEY WORDS:bladder neoplasms, tumor necrosis factor
necrosis factor, which may be a mechanism of action of BCG antitumor activity in superficial bladder cancer. We assess the safety of recombinant h u m a n tumor necrosis have bladder cancer1 and at least 10,000 will die of metastatic disease. Superficial bladder cancer has been treated factor instilled into the bladder, and determine the degree of with a variety of techniques, including transurethral resec- local and systemic toxicity. We were prompted to conduct this tion, fulguration and intravesical chemotherapy or immuno- study i n view of previous animal studies,",'" particularly on therapy.2.3 More than half of the patients who present with cynomolgus monkeys in which doses of recombinant human bladder cancer have superficial disease, with pathological tumor necrosis factor (10 ng. to 1 mg.) were instilled intraevaluation showing equal distribution among grades 1 to 3. vesically and no observable toxicity from treatment was demPatients who have a complete response to transurethral re- onstrated. section andlor fulguration plus intravesical therapy have MATERIAL AND M E T H O D S shown a decreased risk for subsequent invasion or spread. Bacillus Calmette-Guerin (BCG), a n intravesical agent, apPatients who were enrolled in t h e study had to fulfill pears to decrease the recurrence rate of superficial bladder certain criteria. All patients had histologically confirmed cancer. The complete response rate has been reported to be as transitional cell carcinoma, stages 0 or I (Tis, Ta, Tl),and at high as 70%.4.5 The mechanism of action of this biological least 1 of several conditions: greater t h a n 2 recurrences in 1 response modifier is unclear. year, recurrence at 6 months or less after transurethral reIn prospective, randomized trials BCG has been demon- section of bladder tumor, 3 or more lesions present at diagstrated to be superior to other intravesical agents in prevent- nosis, or carcinoma i n situ. All patients had a n Eastern ing recurrence, and treating residual papillary tumors and Cooperative Oncology Group performance status of 0, 1 or 2 carcinoma in situ.6 The optimal BCG dosing schedule, effec- a t most, and all had adequate hematological, renal, coagulative toxicity management and administration strategies have tive and hepatic functions, a s well as a bladder capacity yet to be elucidated. Although the most frequent toxicities of greater than 60 ml. and ability to retain the urine for 2 hours. BCG intravesical therapy are transient, a certain group of Patients may have received prior chemotherapy, immunopatients will have local symptoms, such as bladder pain, too therapy or radiotherapy provided t h a t a t least 2 weeks had severe to continue treatment. Serious complications are rare elapsed from any prior therapy but they must have received but a fatal outcome has been reported.7 intravesical chemotherapy. Tumor necrosis factor was first described by Carswell e t al Patients with urinary extravasation on excretory urograa s a factor isolated from sera of endotoxin treated mice, phy were excluded, a s were those with a history of congestive sensitized previously with BCG.RThe antineoplastic action of heart failure, myocardial infarction within the last 6 months, tumor necrosis factor was confirmed when hemorrhagic ne- a diagnosis of New York Heart Association class 111 or uncrosis of tumor grafts in mice treated with tumor necrosis controlled arrhythmia. Patients were ineligible if they had factor was reported." BCG has been shown to induce tumor significant pulmonary disease, deep venous thrombosis, pulmonary embolus within l year, intermittent claudication, human immunodeficiency virus infection or a known seizure Accepted for publication December 2. 1994. Sup rted in part by National Cancer Institute Investigator disorder, or if they were pregnant or lactating. All patients A w a r r K 0 8 CA 01490 and National Cancer Institute Grants signed a written informed consent. The study chairman CA21115. CA23318, CA31076, CA06594 and CA18653. * Requests for reprints: Section of Hematology/Oncology, Dart- (M. S . E.) was notified before determining eligihility, reverimouth-Hitchcock Medical Center, One Medical Center Drive, Leha- fication and obtaining informed consent. Only after entry non, New Hampshire 03756-0001. onto the working list was the patient evaluated for study. Bladder cancer is the sixth leading cause of cancer death in the United States. In 1994, 51,200 people are expected to
66
67
RECOMBINANT TUMOR NECROSIS FACTOR I N TREATMENT OF BLADDER CANCER TABLE 1. Demoeraohics U
Dose Tier(wz.)
*
No.-Mean
No. Men/ No.Women
.
Tumor Grade
Prior Therapy
Performance Status*
Radiotherapy
'
200
3
0
2
1
0
3
0
400 1,000
3 1
1
0 1
1 1
2 1
3 2
0 1
Chemotherapy
3-69 2/1 3 3-68 310 3 3-7 1 310 3 Eastern Cooperative Oncology Group performance status.
Drug treatment. The recombinant human tumor necrosis factor was supplied through the Cancer Treatment Evaluation Program of the National Cancer Institute, and was administered weekly for I1 weeks in 50 cc of 0.9% (normal) saline with human serum albumin at 2 mg./ml. (100mg.150 ml.). The solution was infused by gravity flow into the bladder through a urinary catheter and was retained in the bladder for 2 hours before emptying. Following completion of the instillations, patients were monitored with cystoscopy and urinary cytology studies every 3 months. An excretory urogram was performed every year. Recurrence was diagnosed by visible tumor on cystoscopy, positive cytology study or bladder biopsy. RESULTS
The 8 men and 1woman studied (mean age 69 years, range 46 to 87) had been treated previously for superficial bladder cancer with transurethral resection of bladder tumors (9),
0
Instillations/
Pt.
Immunetherapy
RS.
'
1 11.11and 11 11, 1 1 a n d 9 4, 11 and 11
TABLE 2. Overall toxicities Dose Tier (crg.) 200
400
LOO0
Flu-like symptoms Headache Liver function tests* Hemet Respiratory tract infection Nausea Vomiting Diarrhea Pelvic pain Chest pain Cystitis Dysuria Bladder pain Urethritis Frequency
2 (1)
-
-
1(2) l(1) l(1)
l(1)
-
l(1) chemotherapy (9) and radiotherapy (1).No patient had rel(2) sidual tumors at initiation of intravesical therapy. Patients Values are given 88 toxicity grade (numberof patients). in each dose cohort were of excellent Eastern Cooperative * Altered liver function tests, grade 1.2.5 or less x Y CY = upper limit of Oncology Group status and similar mean age. The prepon- normal). derance of male patients reflects the distribution of the dist Altered hematological indexes, white blood cell value grade 1, 3.0 to 3.91 ease between the sexes. Table 1 shows the demographic 111111.3. makeup of the population. The overall toxicity and frequency of these events according to the National Institutes of Health common toxicity scores, as well as the urological toxicities TABLE3. Followup after transurethml resection of bladder tumor encountered are shown in table 2. In 5 of 9 patients mild and recombinant human tumor necrosis factor treatment urological symptoms occurred that could be related to cathNo. pta. (toxicity grade) eterization andor recombinant human tumor necrosis factor. Dose Tier No. pts. (M.) No Evidence of Regressive Also, mild flu-like symptoms were reported in 5 of the 9 Disease Disease patients and these occurred at all dose levels, suggesting a 200 systemic effect of intravesical recombinant human tumor 400 necrosis factor. Hematological and gastrointestinal toxicities LOO0 were minor, and no renal toxicity was encountered. The trial was discontinued at a 1,000 pg. recombinant human tumor necrosis factor dose tier, which was believed not to exceed clinical relevant dosages. Table 3 outlines patient response at remain tumor-free at 3 years and 90%with recurrent disease followup aRer transurethral resection of bladder tumors and at 3 months will continue to have recurrences for 3 years.13 recombinant human tumor necrosis factor treatment. BCG, thiotepa, mitomycin C and doxorubicin are some of One patient withdrew from the study after only 4 instilla- the more common agents used for intravesical therapy that tions and relapse was noted at followup cystoscopy. A total of have resulted in a decrease in recurrence rates.14-17 Inter8 patients had a complete response after transurethral re- feron in the prophylactic treatment of bladder cancer has section of bladder tumors and tumor necrosis factor treat- been shown to be less effective than mitomycin but it is better ment but all had relapse at a mean of 16 months (range 7 to tolerated.18 When used prophylactically, BCG has been 35). shown to be the most effective agent in preventing recurrences when coupled with transurethral resection of bladder DISCUSSION tumors, with cure rates of approximately 70%.16.19 The mechThe majority (75 to 85%) of bladder cancers are superficial anism of action of BCG is not fully understood. It has been in nature." Treatment is focused on 3 distinct goals, that is postulated that BCG may act by local imtation or through a to eliminate existing disease, prevent recurrence of tumor vaccination-type response. It is known that cytokine release and impede progression to muscle invasion or metastasis. has been associated with BCG therapy. Recombinant human The gold standard for initial treatment of superficial cancer tumor necrosis factor is a cytokine induced by BCG therapy. Tumor necrosis factor is a naturally occurring product is transurethral resection of bladder tumors. Heney et al reported that stage T1 tumors recurred in 70%of the patients known to stimulate natural killer and lymphokine-activated after 3 years and stage Ta tumors recurred in 55%.12 These killer cells, as well as to modulate granulocytes and Bcell recurrences are treated with transurethral resection of blad- function. Tumor necrosis factor is an antitumor agent that der tumors. Of patients with stage Ta, grade 1tumor who do has been shown in vitro to be cytotoxic and cytostatic, and it not have a cystoscopic recurrence at 3 months, 80% will appears to inhibit cell proliferation during the G2 phase of
68
RECOMBINANT TUMOR NECROSIS FACTOR IN TREATMENT OF BLADDER CANCER
the cell cycle.20 It has been suggested, based on mouse studies in which recombinant human tumor necrosis factor was associated with hemorrhagic necrosis of tumors, that tumor necrosis factor mediates endotoxin-induced tumor necrosis and may be linked to the suppression of transformed cells by activated macrophages.8 Bahnson and Ratliff confirmed that recombinant human tumor necrosis factor in conjunction with doxorubicin has antitumor activity in the mouse bladder tumor model in vitm but was ineffective in decreasing implantation of intravesical tumors in vivo.*o The wide varieties of toxicities reported with the systemic use of recombinant human tumor necrosis factor have not been confirmed in our intravesical studies. The maximum tolerated dose was not achieved. Further study of recombinant human tumor necrosis factor may be necessary, since the issue regarding the safety and toxicity spectrum of recombinant human tumor necrosis factor as a single agent when used intravesically has been determined. Given the interactions between tumor necrosis factor and chemotherapy agents, most noticeably mitomycin C and doxorubicin, a rational approach would be to combine these agents for intravesical use. Another rational approach is to combine tumor necrosis factor with other biological agents, specifically BCG or interferon-&.We have no evidence of efficacy for intravesical recombinant human tumor necrosis factor in the treatment of superficial bladder cancer and a larger phase I1 study should be performed, following which rational drug development can proceed. REFERENCES
1. Boring, C. C., Squires, T. S., Tong, T. and Montgomery, S.: Cancer statistics. CA, 44:7, 1994. 2. Soloway, M. S.: Rationale for intensive intravesical chemotherapy for superficial bladder cancer. J. Urol., 123: 461,1980. 3. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116 180, 1976. 4. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and as&ated immune responses. Cancer, 48.82, 1981. 5. Pinsky, C., Camacho, F., Kerr, D., Herr, H., Geller, N., Whitemore, W. and Ottegen, H.: Treatment of specified bladder cancer with intravesical BCG. Proc. Amer. Soc. Clin. Oncol., 2 57, 1983. 6. Guinan, P., Richardson, C., Hanna, M. and Rubenstein, M.: BCG in the management of superficial bladder cancer. Prog. Clin. Biol. Res., so9: 447, 1989. 7. Rawls, W. H., Lamm, D. L., Lowe, B. A., Crawford, E. D., Sarosdy, M. F., Montie, J. E., Grossman, H. B. and Scardino, P. T.: Fatal sepsis following intravesical bacillus CalmetteGuerin administration for bladder cancer. J. Urol., 144: 1328, 1990. 8. Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N. and Williamson, B.: An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl. Acad. Sci., 7 2 3666, 1975. 9. Bahnson, R. R., Ballou, B. T., Emstoff, M. S., Cramer, D. V., Schwentker, F. N., Reiland, J. M. and Hakala, T. R.: Toxicity of intravesical recombinant human tumor necrosis factor in cynomolgus monkeys. J. Biol. Resp. Mod., 9: 445, 1990. 10. Bahnson, R. R. and Ratliff, T. L.: In vitro and in vivo anti-tumor
activity of recombinant mouse tumor necrosis factor (TNF) in a mouse bladder tumor (MBT-2). J. Urol., 144: 172, 1990. 11. Herr, H. W., Laudone, V. P. and Whitmore, W. F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol., 138 1363, 1987. 12. Heney, N. M.. Ahmed, S., Flanagan, M. J., Frable, W.,Corder, M. P., Hafermann, M. D. and Hawkins, I. R. for National Bladder Cancer Collaborative Group A Superficial bladder cancer: progression and recurrence. J. Urol., 130 1083, 1983. 13. Fitzpatrick, J. M., West, A. B., Butler, M. R., Lane, V. and OFlynn, J. D.: Superficial bladder tumors (stage pTa. grades 1 and 2): the importance of recurrence pattern following initial resection. J. Urol., 135: 920, 1986. 14. Koontz, W. W., Jr., Prout, G. R., Smith, W., Frable, W. J. and Minnis, J. E.: The use of intravesical thio-tepa in the management of non-invasive carcinoma of the bladder. J. Urol., 12& 307, 1981. 15. Martinez-Piiieiro, J. A.: BCG vaccine in superficial bladder tumors: eight years later. Eur. Urol., 1 0 93. 1984. 16. Lamm, D. L., Crissinam, J., Blumenstein, B. A,, Crawford, E. D., Montie, J., Scardino, P., Grossman, H. B., Stanisic, T., Smith, J., Sullivan, J. and Sarosdy, M.: Adriamycin vs. BCG in superficial bladder cancer. A Southwest Oncology Group Study. In: BCG in Superficial Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meivden. New York: Alan R. Liss. Inc., pp. 263-270, 1989. 17. Irwin, R.. Zincke, H., Droller, M. J., Prout. G. R.. Jr. and Soloway, M. S.: Treatment modalities in superficial bladder cancer. Sem. Urol., suppl., 7: 1, 1989. 18. Boeeardo, F., Cannata, D., Rubagotti, A., Guameri, D., Decensi, A., Canobbio, L., Curotto, A,, Martorana, G., Pegoraro, C., Silvaggi, F., Salvia, G., Comeri, G., Bono, A., Borella, T. and Giuliani, L.: Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of a multicentric Italian study. J. Clin. Oncol., 12 7, 1994. 19. Herr, H. W.: Intravesical therapy. Hematol. Oncol. Clin. N. h e r . , 6: 117, 1992. 20. Darzynkiewicz, Z., Williamson, B., Carswell. E. A. and Old, L. J.: Cell cycle-specific effects of tumor necrosis factor. Cancer Res., 44 83, 1984. ~~~
EDITORIAL COMMENT
This phase I protocol seeks to optimize the dose and establish toxicities for the cytokine recombinant human tumor necrosis factor. Phase I clinical trials in superficial bladder cancer are unusual and require that patients entered have exhausted standard immunotherapeutic as well as chemotherapeutic regimens, and have a marker lesion in the bladder. This marker lesion is used to evaluate antineoplastic activity of the agent being evaluated in phases I and II clinical trials. In this trial a 1,000 pg. dose of this biological response modifier was well tolerated. As with many of the biological agents used in the treatment of superficial bladder cancer, the limiting dose is frequently dictated by the cost of the agent. Large doses of interferon exceeding 100 million IU can be administered with little to no toxicity. This clinical trial, as well as one that we have completed, establish the safety and, to some degree, the anti-cancer activity of the drug. Further clinical trials should proceed with this agent, perhaps combining it with other biological agents, alternating therapy with established chemotherapeutic drugs or as a single agent comparing it ta BCG or mitomycin C.
E. David Crawford Division of Urology University of Colorado Denver, Colorado