Annals of Oncology 3: 741-745,1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Original article Recombinant tumor necrosis factor for superficial bladder tumors C. N. Sternberg,1 M. G. Arena,1 V. Pansadoro,2 F. Calabresi,1 I. D'Agnano,1 P. De Carli,1 M. Zeuli,1 A. Cancrini,1 F. Rosenkaimer3 & G. Zupi1 'Regina Elena Cancer Institute; 2CTO Hospital, Rome, Italy, and 'Boehringer Ingelheim International GmbH, lngelheim, Germany

Summary. Twenty patients with histologically documented superficial bladder cancer (Ta, Tl, Tis) were treated with intravesical administration of TNF 400-1800 micrograms. Of 18 patients with a marker lesion, 2 obtained a complete response for 8+ and 18 months. Two had a partial response and were given other intravesical therapies after 5 and 7 months. No or minimal systemic absorption of TNF was observed and documented in 4 of 20 patients by pharmaco-

kinetic studies, and no patients developed antibodies to intravesically administered TNF. TNF was well tolerated in doses up to 1800 micrograms. No systemic or local side effects were observed. Modest activity was attained with intravesical TNF, even in pretreated patients. Key words: TNF, superficial bladder tumors, intravesical therapy

found in the serum of animals treated with endotoxin after priming with immunomodulators such as BCG or Superficial bladder tumors include a spectrum from CParvum [6]. In the initial work on TNF, Old and collow grade, low stage papillary tumors (Ta-mucosaL, or laborators hypothesized that TNF was the product of Tl-submucosal) to high grade flat carcinoma in situ. activated macrophages. They subsequently showed that They have a variable biologic potential for recurrence, partially purified TNF could not only induce hemorinvasion and subsequent metastases [1, 7]. After trans- rhagic necrosis in the transplantable Meth A sarcoma urethral resection, intravesical therapy is used thera- model but also had in vitro antitumor activity against peutically to eradicate existing disease and adjuvantly human melanoma cells [11]. Its apparent specificity for or prophylactically to prevent recurrence or progres- transformed cells generated considerable interest in its sion [1]. use in the treatment of cancer. Recombinant DNA Intravesical therapy has assumed increasing impor- methodology has allowed production of large quantitance by virtue of its ease of administration, minimal ties of purified TNF, now available for clinical trials. In systemic toxicity and ability to deliver high drug con- vitro cytostatic and cytotoxic effects against a wide centrations at the target area [1-3]. In both randomized range of human tumor cells have been shown. Direct and non-randomized trials, intravesical chemotherapy cytotoxic effects against murine bladder tumors, and and immunotherapy, particularly thiophosphoramide, synergy with chemotherapy against bladder cancer cell mitomycin-C, epodyl, doxorubicin, and BCG have lines have been demonstrated [12,13]. been shown to be variably efficacious. BCG is probably A clinical trial was initiated in order to study the the most active agent [1]. tolerance of TNF given intravesically twice a week and BCG therapy induces granulomatous cystitis which to determine the systemic absorption of TNF after can cause low grade fever, pain and dysuria. It has been intravesical administration in patients with superficial postulated that the efficacy of BCG is in part due to the bladder cancer. Though not an initial intention of this local production of immunomodulatory cytokines [4]. phase I study, when possible, a marker lesion was left in One such cytokine, tumor necrosis factor (TNF) has place, and the antitumor effect of intravesical TNF was been shown to be induced by BCG in animal studies [4, evaluated. Ethical committee approval was obtained for 5]. Intravesical BCG therapy may result in the recruit- the conduct of this protocol. Verbal informed consent ment and activation of CD4+ T cells to the bladder was obtained in all patients, and a copy of the Helsinki with an increase in both constitutive and interleukin-2 agreement was signed by the responsible physician. triggered TNF production which may be associated with the positive anti-tumor effects of BCG [7]. In addition, the known direct antitumor effect of TNF pro- Materials and methods vides the rationale for its evaluation in superficial blad- Patients were eligible for this study who had a histologically docuder cancer [8-10]. mented superficial bladder cancer (Ta, Tl, Tis) and a Karnofsky TNF was initially described as the antitumor activity Performance Status of >60. Entry occurred within 2 weeks after Introduction

742 transurethral resection (TUR) in most patients, and prior to 42 days after cystoscopy or TUR in all cases. In addition to the TUR, prior to therapy all patients, had a urinary cytology, urinanalysis, and urine culture if urinary symptoms were present. Flow cytometric analysis of DNA content was performed on ten patients. Entry criteria included a creatinine

Recombinant tumor necrosis factor for superficial bladder tumors.

Twenty patients with histologically documented superficial bladder cancer (Ta, T1, Tis) were treated with intravesical administration of TNF 400-1800 ...
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