Intravesical Therapy for Superficial Bladder Cancer

Introduction

Transitional cell carcinoma of the bladder remains a significant health problem in the United States. Approximately 54,400 new cases of transitional cell carcinoma were reported in the United States in 1999, and an estimated 12,500 deaths were attributed to this cancer.[1] These statistics have remained relatively unchanged over the last several decades despite improvements in both diagnostic instrumentation and therapeutic intervention, as well as greater awareness of cigarette smoking and occupational chemical exposure as important risk factors.

The prevalence of transitional cell carcinoma is at least 400,000 cases. The disease represents the fourth most common neoplasm in males and the eighth most common malignancy in females. The incidence of bladder cancer is four times higher in men than it is in women. The median age at diagnosis is 65 years.[2]

The majority of transitional cell carcinomas are papillary in morphology and are derived from the urothelium. At initial presentation, 70% of these tumors are superficial, defined as involving the mucosa (epithelium) or submucosa (lamina propria) only (stage Ta, T1, or Tis).

The natural history of superficial transitional cell carcinoma is still largely unpredictable because of tumor heterogeneity, as well as the multifocal nature of the disease. Tumors recur in 40% to 80% of patients and progress in 5% to 30%, despite complete resection. In general, superficial transitional cell carcinoma, when it does recur, remains stable with regard to stage and grade. Yet, in selected cases, the risk of progression to a muscle-invasive tumor is as high as 50% to 80%. The two basic categories of risk factors are tumor burden and dedifferentiation.[3]

Transitional cell carcinoma in situ (Tis) histologically consists of poorly differentiated transitional cell carcinoma confined to the urothelium. Frequently associated with high-grade yet superficial papillary tumors, Tis portends a poor prognosis. Patients with carcinoma in situ have the highest recurrence rate. When treated with endoscopic resection alone, between 40% and 80% of these patients will progress to high-stage, muscle-invasive transitional cell carcinoma.

The time to progression to muscle-invasive disease remains unpredictable; however, patients with marked voiding symptoms, which implies increased tumor burden, clearly have a shorter interval preceding the development of invasive tumor. As many as 20% of patients with diffuse Tis are found to have evidence of muscle invasion on final pathologic examination when ultimately treated with radical cystectomy. Furthermore, as many as 10% of those patients with only focal Tis are found to have occult regional metastases at the time of radical surgery.[4,5]

Treatment Approach

Transurethral resection of all visible transitional cell carcinoma (when possible) remains the ultimate method of pathologic staging and primary treatment. Pathologic review and appropriate additional clinical staging are required to identify patients at risk for recurrence and those for whom intravesical treatment is appropriate.

In patients with low-grade, low-stage, small-volume disease, careful surveillance endoscopy and intermittent resection or fulguration alone may be sufficient. In patients with higher-grade tumors, large-volume, and/or multifocal disease, adjuvant therapies should be considered.[6]

Adjuvant intravesical therapy, whether in the form of chemotherapeutic or immunologic agents, is indicated in patients at high risk for tumor recurrence. High-risk patients include those with multiple or large tumors at initial resection, tumor recurrence(s), high-grade tumors, or papillary tumors associated with carcinoma in situ, as well as those with carcinoma in situ without papillary transitional cell carcinoma.

When intravesical agents are used to destroy residual transitional cell carcinoma following incomplete resection, the treatment is considered to be therapeutic in nature. However, when the agents are selected after complete resection of all visible tumor, treatment is defined as prophylactic.

Chemotherapeutic agents that have historically been used for treating superficial transitional cell carcinoma of the bladder include thiotepa(Drug information on thiotepa) (triethyl-enethiophosphoramide [Thioplex]), mitomycin(Drug information on mitomycin) (Mutamycin), doxorubicin(Drug information on doxorubicin), epirubicin(Drug information on epirubicin) (4¢-epidoxorubicin [Ellence]), and, most recently, valrubicin (N-tri-fluoroacetyladriamycin-14-valerate [Valstar]). Biological therapies employing immunologically active agents include bacillus Calmette-Guérin (BCG), bropiramine (2-amino-5-bromo-6-phenyl-4-[3H]-pyrimidinone), recombinant interferon-alfa-2b (Intron A), and photosensitizers combined with laser therapy.

It remains a peculiarity of urologic practice that many agents commonly used to treat bladder cancer have never actually been approved by the Food and Drug Administration (FDA) for that specific use. This is especially relevant when discussing the management of intravesical treatment of superficial transitional cell carcinoma of the bladder. The only agents approved by the FDA for use in patients with transitional cell carcinoma are thiotepa, BCG, and valrubicin. Thiotepa was approved only for the treatment of low-grade, low-stage papillary transitional cell carcinoma, whereas bacillus Calmette-Guérin was approved only for patients with Tis. Valrubicin recently received FDA approval only for the treatment of refractory Tis.

Yet, in most urologic practices, the “off-label” use of these agents frequently benefits the patient. For example, BCG is used as a first-line therapy for both papillary transitional cell carcinoma and Tis despite the fact that it has been approved only for the management of Tis. In addition, a number of other options are available for patients who do not respond to or cannot tolerate intravesical BCG.

Immunologic Agents

BCG

Although not yet completely understood, the mechanism of BCG, and, indeed, of all biologically active agents, is immunomodulation. It appears that the mycobacteria of BCG attach to the surface epithelium of the bladder tumor and normal bladder; this attachment is facilitated by fibronectin. The mycobacteria are subsequently internalized and form complexes with various glycoproteins; the mycobacteria-glycoprotein complexes presumably stimulate a T-cell–mediated immune response. In addition, BCG directly activates macrophages, T and B lymphocytes, and natural killer cells, as well as antibody-dependent killer cells. These factors then activate lymphokine and interferon production.

Bacillus Calmette-Guérin should not be administered to immunocompromised hosts, patients receiving therapeutic (rather than replacement) exogenous steroids, those who have had a traumatic catheterization, or those with persistent gross hematuria following bladder tumor resection. Patients with gross hematuria at the time of catheterization are at greatest risk for the development of systemic BCG-induced infection and possibly death.[7]

Interferon

Since interferon is clearly one of the end products of successful BCG treatment of superficial transitional cell carcinoma, it would seem logical that direct instillation of interferon into the bladder should also control this cancer. Various subtypes of interferon have, in fact, been used, unfortunately with only limited effect.

Recombinant interferon-alfa-2b has demonstrated some efficacy in the treatment of Tis in clinical trials. The appropriate intravesical dosage seems to be in the range of 50 to 100 million units administered weekly for 6 weeks. Durable responses to interferon, however, are clearly less impressive than with BCG, possibly indicating that some other factor or combination of factors, such as the cell-mediated cascade, is necessary for a maximal beneficial effect. Also, intravesical interferon-alfa-2b seems to be more effective when used as initial treatment, rather than as a salvage regimen in patients who have not responded to BCG.[8]

In an earlier study looking at doses of interferon-alfa-2b, patients treated with a high dose (100 million units) had clearly superior responses than those given a low dose (10 million units). Interestingly, however, six of the nine patients in this study had proved unresponsive to prior intravesical BCG therapy, and maximum follow-up was only 12 months.[9]

Greenberg is currently conducting a phase II trial to determine whether the combination of BCG plus interferon-alfa-2b is more effective than either agent alone. Other investigators are attempting to define the best possible dose of BCG and interferon-alfa-2b when used in combination. There is ample clinical as well as laboratory evidence that, with biologically active agents, more is not always better, and lower- dose combinations may not only keep the cost of these treatments down but also yield superior results.[9,10]

Other Immunomodulators

Other immunomodulators that have been evaluated in the management of transitional cell carcinoma include bropiramine and TP-40.

Bropiramine is an oral inducer of interferon and other cytokines that can activate several related immunologic defense mechanisms.[11,12] Initial reports indicated exceptional response rates, especially in patients with stage Tis disease. Among this latter group, biopsies and bladder wash cytologies became negative in 61% of patients, including complete responses in 50% to 60% patients who had received prior BCG treatment. Complete responses occurred in 60% to 70% of patients who had not received prior BCG treatment and 80% of patients with primary Tis cancers (de novo tumors not associated with papillary disease).[11]

Subsequent, careful monitoring failed to demonstrate sufficient efficacy of bropiramine to win FDA approval, however. In addition, significant cardiac-related toxicity was associated with this treatment, and it is currently no longer in clinical trials or available for general use.

TP-40, a Pseudomonas exotoxin, was used in phase I research studies and found to have excellent response in patients with stage Tis bladder tumors, although little or no activity against superficial papillary transitional cell carcinoma. Since no apparent toxicity was uncovered in this phase I study, the maximum tolerated dose was not determined.[13] Unfortunately, despite the promise of TP-40 in patients with BCG-refractory Tis, phase II studies of this agent have not been initiated.

Photodynamic Therapy

A number of recent reports have demonstrated a possible role for photodynamic therapy (PDT) in the treatment of recurrent Ta, T1, and Tis transitional cell carcinoma. Photodynamic therapy is a form of cancer treatment based on the destruction of cells by the interaction of light (400 to 760 nm) with a photosensitizing dye and oxygen. When administered systemically, these substances accumulate in both tumor and normal tissues. Upon exposure to light of an appropriate wavelength, based on the nature of the specific photosensitizing agent, an in situ chemical reaction ensues. The ultimate effect is the local production of reactive oxygen radicals that are cytotoxic.

First-generation photosensitizers caused prolonged phototoxicity and had inferior tumor specificity, resulting in accumulation within the detrusor muscle with subsequent permanent loss of bladder capacity and acute post-PDT syndrome, characterized by frequency, urgency, nocturia, and bladder spasms.[14] Since the tumor cells preferentially take up the newer photosensitizing agents, these drugs appear to have a more specific cytotoxic effect against the malignant cells and, thus, less toxicity. A newer agent, 5-aminolaevulinic acid (ALA), generates a photosensitizer called protoporphyrin IX (PpIX), which has fewer side effects and a much shorter period of systemic phototoxicity than previous photosensitizing agents.

Patients with resistant superficial bladder cancer who were treated with prophylactic whole-bladder PDT demonstrated complete response rates at 3 months of 84% and 75% for residual-resistant papillary transitional cell carcinoma and refractory Tis, respectively. At a median of 50 months, 59% of responding patients were alive, and 31 of 34 responders remained disease free.[15]

In a similar study, 36 patients with BCG-refractory Tis demonstrated a complete response rate of 58% at 3 months with a durable response rate (no tumor recurrence at 12 months) of 31%.[16] At 12 months, 14 patients subsequently underwent cystectomy, 12 for persistent disease and 2 for a recurrence. Most patients initially diagnosed with Tis who subsequently developed a recurrence following whole-bladder PDT were easily managed with trans-urethral resection for superficial recurrence only.

Thus, it seems obvious that, in some patients, altering the expected natural history of the transitional cell carcinoma represents a beneficial outcome.