Home

HPV na Prática Clínica

Conheça a clínica
Corpo clínico
Fale Conosco

Doenças e Disfunções
.Infertilidade
.Disfunção erétil
.Infecção urinária
.DST
.Próstata
.Rim
.Bexiga
.Testículos
.Pênis
.Cálculos urinários
.Vasectomia
.Reversão de Vasectomia

Compre o livro
HPV na Prática Clínica

Mapa de acesso ao consultório

Intravesical Therapy for Superficial Bladder Cancer CME

Ashish M. Kamat, MD, Donald L. Lamm, MD, West Virginia University School of Medicine, Morgantown, W. Va.

Abstract
Currently, bacillus Calmette-Guérin vaccine (BCG) immunotherapy remains the most effective intravesical therapy for treatment and prophylaxis of transitional cell carcinoma (TCC) of the bladder, stage Ta, T1, and carcinoma in situ (CIS). It has been used successfully to reduce tumor recurrence rates and disease progression and to prolong survival. Recent evidence from a double-blind, controlled trial suggests that results of BCG therapy can be further improved by concomitant use of megadose vitamins. Interferons, Keyhole Limpet Hemocyanin (KLH), and Photofrin Photodynamic Therapy are other alternatives for the management of TCC that are under investigation; the efficacy results are encouraging.

Introduction
Bladder cancer is the fourth most common cancer among men and the eighth most common cancer among women, accounting for 5.5% and 2.3% of all cancer cases, respectively.[1] In 1997, it was estimated that 54,500 new cases of bladder cancer would be diagnosed and 11,700 bladder cancer deaths would occur annually.[2] Although the incidence of bladder cancer in the US has been increasing, mortality rates declined by 8% between 1980 and 1995.[3] This has been largely attributable to improvements in intravesical therapy of superficial bladder cancer. We review the role of intravesical immunotherapy in the management and prophylaxis of superficial transitional cell carcinoma (TCC) of the bladder.

Indications for Intravesical Therapy
The 3 main objectives that guide the use of intravesical therapy of superficial bladder cancer are: to treat existing tumor or carcinoma in situ, to prevent recurrence in a bladder rendered free of tumor, and to prevent progression of disease. Prior to initiating intravesical therapy, an attempt to minimize the extent of disease by resection and fulguration should be made, since a low tumor burden increases the chances of therapeutic success.
When selecting among the various intravesical treatments, the proposed benefits and the expected risks of each course must be considered. Since most agents used currently are well tolerated, the decision rests primarily on the behavior of the patient's particular type of tumor. Patients who fail one type of intravesical therapy may be managed with another agent.
TCC of the bladder can be divided into 2 categories: superficial tumors and muscle-invasive tumors. Superficial TCC tumors are those that have not invaded the muscularis propria, regardless of grade. They include papillary lesions confined to the urothelium that do not penetrate the basement membrane (Ta), tumors with invasion into the lamina propria (T1), and carcinoma in situ (CIS). At the time of diagnosis, 64% to 80% of cases are superficial; of those, 70% are stage Ta and 30% are stage T1.4 Despite complete resection, recurrence rates are 66% at 5 years and 88% at 15 years.[5] Progression from superficial bladder cancer to deep muscle invasion occurs in 15% of patients.[6]
Low-grade Ta lesions have a low progression rate (7% at 7 years), and intravesical therapy is not necessarily required for the treatment of primary low-grade, stage Ta disease when other risk factors for progression are not present. However, the EORTC/MRC (European Organization for Research and Treatment of Cancer/Medical Research Council) reported a 12% reduction in tumor recurrence in such patients when treated with a single early postoperative instillation of epirubicin (a doxorubicin-related agent).[7] Multifocal Ta disease with or without CIS is a relative indication for intravesical therapy.[8] Infrequent recurrence and progression of low-grade stage Ta disease might be repeatedly treated with transurethral resection (TUR) alone. However, when recurrence is noted within 2 years, intravesical therapy should be considered.
With invasion of the lamina propria, tumor cells have access to blood and lymphatic channels, thus allowing for metastatic spread. Grade is an important cofactor when considering the progression of T1 lesions.[9] Regardless of grade, however, stage T1 disease has a propensity to invade, and the reported overall progression rate of 29% for T1 tumors warrants intravesical therapy.[10]
Although unpredictable, CIS has a risk of disease progression of 54% at 5 years.[11] The presence of even a small focus of CIS is a definite indication for intravesical therapy. Intravesical immunotherapy is now the first-line treatment for diffuse CIS and has replaced cystectomy as the initial therapy.
Grade III tumors have a 70% risk for recurrence and a 45% risk for progression at 3 years.[12] Therefore, grade III disease, regardless of tumor stage, is an indication for intravesical therapy. Also, for Ta and T1 tumors, the best predictor of cancer-specific death is the presence of grade III disease; therefore, these patients should be offered intravesical therapy.
Multifocal superficial disease is also associated with an increased risk of progression and constitutes another indication for adjuvant intravesical therapy. Positive postresection cytology suggests incomplete tumor resection, implantation of tumor cells during resection, tumor recurrence, extravesical tumor, urothelial dysplasia, or CIS. Intravesical therapy should be considered in these patients because of the high risk of tumor recurrence.
Prostatic urethral involvement with CIS carries a high risk of progression and poor prognosis and should be treated aggressively. The use of intravesical bacillus Calmette-Guérin (BCG) immunotherapy has obviated the need for cystectomy in many of these patients.[13] TUR is recommended to open the bladder neck in order to allow BCG to bathe the prostatic urethra.

Intravesical Chemotherapy

Thiotepa
Thiotepa, or triethylenethiophosphoramide, is an aziridine with trifunctional alkylating activity. The alkylating action leads to interstrand cross-linking of DNA, which leads to eventual cell death. Thiotepa is useful in the treatment of residual tumor and CIS and for the prevention of tumor recurrence. As a therapeutic agent, a complete response occurs in one third of patients, while one third show no response. Six of 10 randomized, controlled studies of thiotepa as a prophylactic agent have shown statistically significant reduction of tumor recurrence with thiotepa instillation.[11,14] Although a decrease in recurrence of 0% to 41% has been reported, the overall reduction with thiotepa compared with controls averaged 12%.[14] Although not proven conclusively, protocols using early administration (within 3 days of tumor resection) generally report better results. It is theorized that early instillation may destroy tumor cells disseminated during TUR and thereby prevent implantation.
The standard protocol for intravesical therapy with thiotepa consists of 4-6 weekly treatments of 30mg in 30cc of sterile water. However, multiple treatments have not been demonstrated to be superior to a single instillation. After instillation the drug is kept in the bladder for 2 hours, during which time the patient may lie prone for 15 minutes to displace the air bubble at the bladder dome and ensure contact of thiotepa with the urothelium at the dome. Animal studies, however, have suggested that this may be unnecessary.[15] Thiotepa is generally well tolerated. Mild cystitis after treatment and irritative voiding symptoms occur in 15% to 30% of patients. The major adverse effect of thiotepa is myelosuppression due to systemic absorption. The incidence of leukopenia ranges from 8% to 54%, with an average of 16%; that of thrombocytopenia ranges from 3% to 31%.[16] Recent tumor resection, extensive tumor, or concurrent cystitis can markedly increase absorption. WBC count and platelet count should be checked prior to each treatment. When intravesical thiotepa is administered with these precautions, it is safe and effective.

Doxorubicin
Doxorubicin, produced by Streptomyces peucetius, is an anthracycline antibiotic that has broad chemotherapeutic activity. Anthracycline antibiotics disrupt the cell by several mechanisms, including intercalating between DNA base pairs; inactivating DNA topo-isomerase II, which results in DNA strand breaks; and producing activated oxygen radicals, which leads to membrane disruption. The average decrease in tumor recurrence is 13% and, at 5 years, an estimated 17% of patients with stage Ta or T1 disease who receive doxorubicin intravesically remain free of disease.[13]
Administration of intravesical doxorubicin is similar to that of thiotepa. Doses ranging from 30mg to 90mg at a concentration of 1mg/mL have been used with no significant difference in efficacy. The maximal benefit in reported controlled prophylaxis studies occurred with a single, early, postoperative instillation; maintenance therapy has not shown any added benefit. The primary side effect is chemical cystitis. Symptoms of dysuria, frequency, and urgency occur in up to 50% of patients. Rarely, permanent bladder contracture may result. Systemic hypersensitivity reactions following administration of intravesical doxorubicin also have been reported.[17]

Mitomycin C
Mitomycin also belongs to the class of antibiotic chemotherapeutic agents, and is produced from Streptomyces caespitosus. After cellular uptake, mitomycin is reduced to a mono- or bifunctional alkylating agent, which leads to cross-linking of DNA and inhibition of DNA synthesis. Mitomycin is more widely used than doxorubicin. Complete response is seen in an average of 49% of patients with Ta and T1 disease. The average decrease in recurrence was 15%.[18]
Most mitomycin instillation protocols have used 20mg to 60mg weekly for 6 to 8 weeks. There are presently no studies that show that long-term therapy is significantly better than short-term therapy. The major adverse effect of intravesical mitomycin is chemical cystitis, which occurs in up to 41% of patients.[19] Although considered the least toxic intravesical therapy, irritative voiding symptoms may be so severe that patients refuse further therapy. In 1 report, decreased bladder capacity occurred in 22% of patients; 2 of 76 patients required cystectomy for severe bladder contracture.[20] Skin rash in a palmar and facial distribution as well as palmar desquamation have also been reported.

Other Chemotherapeutic Agents

Ethoglucid/Epodyl
Ethoglucid or Epodyl, triethylene glycol diglycidyl ether, is a diepoxide with alkylating activity similar to that of thiotepa. Robinson and colleagues[21] reported a complete response rate of 35% in treating papillary disease. In a randomized comparison trial of ethoglucid and doxorubicin, Kurth and associates[22] reported that ethoglucid was more effective than intravesical doxorubicin or TUR alone. Ethoglucid decreased the recurrence by 31%, while doxorubicin decreased recurrence by 13% compared with controls. Chemical cystitis with frequency, dysuria, and urgency was reported in 59%, bone marrow suppression in 4%, and reduced bladder capacity in 19%.[21] Others have not reported systemic toxicity; adverse reactions were limited to cystitis or allergic reaction.[18]
Epirubicin Hydrochloride
Epirubicin hydrochloride, 4'-epidoxorubicin, an epimer of doxorubicin, differs from doxorubicin only in the stereochemistry of the daunosamine sugar side chain. The mode of antitumor action of epirubicin is similar to that of doxorubicin, as are the adverse effects. In a study of 399 randomized patients with solitary tumors, a single postoperative instillation of 80mg within 6 hours of tumor resection reduced tumor recurrence by 12% compared with surgery alone.[7]

Mitoxantrone
Mitoxantrone (dihydroxyanthracenedione) is a synthetic antineoplastic compound which structurally simulates doxorubicin. It is presently under investigation as an intravesical chemotherapeutic agent,[23] but has been used to treat acute myelogenous leukemia. The mode of action of mitoxantrone is not completely understood, but it does inhibit both RNA and DNA synthesis, and is known to intercalate within DNA, as does doxorubicin. Serreta and coworkers[24] reported that chemoprophylaxis with mitoxantrone for Ta and T1 disease reduced tumor recurrence in 50% of patients, with a mean recurrence rate of 0.56 per year. Mitoxantrone appears to have an acceptable safety profile; the primary toxic effect is chemical cystitis, reported in 26% of patients.

Long-term Benefits of Intravesical Chemotherapies
With the exception of ethoglucid compared with doxorubicin,[22] controlled comparisons of intravesical chemotherapies have failed to demonstrate any significant difference in their ability to reduce recurrence. Short-term recurrence has been reduced by 12% to 31%: 12% with thiotepa, 13% with doxorubicin, 15% with mitomycin C, and 31% with ethoglucid. Long-term (>=5 years) reduction of tumor recurrence has been difficult to assess. Prout and associates[25] reported equivalent 5-year recurrence in patients treated with thiotepa versus surgery alone. Akaza and colleagues[26] reported 6-year follow-up of a prospective, randomized study with intravesical mitomycin versus doxorubicin versus control and found no significant effect of chemotherapy versus control with respect to recurrence index or mean time between recurrences. However, the combined EORTC/MRC meta-analysis of more than 2500 patients reported a 7% reduction in tumor recurrence at 7 years in patients given adjuvant intravesical chemotherapy versus patients treated with surgery alone. Unfortunately, no clear advantage of adjuvant treatment was shown with respect to progression to invasive disease, time to appearance of distant metastases, or duration of survival.[27]
Although intravesical chemotherapy has demonstrated reduction in short-term tumor recurrence rates, it has not altered disease progression. Progression data are available for more than 3000 patients enrolled in prospective, controlled chemotherapy studies.[5] No statistically significant reduction was reported in the risk of disease progression with the use of thiotepa, doxorubicin, mitomycin, or epirubicin. Moreover, the mean rate of progression for those treated with intravesical chemotherapy was 8.3%, versus 8.6% for the control groups.[18] Intravesical chemotherapy has some efficacy in the management of CIS, with reported overall complete response rates of 34%.[5]
Traynelis and Lamm[18] reported that for 3614 patients enrolled in controlled chemotherapy trials, the overall average reduction in tumor recurrence at 1 to 3 years was 14%. Of the 22 reviewed clinical trials, 10 failed to demonstrate any statistically significant reduction in tumor recurrence. This very modest reduction in short-term recurrence would be worth the morbidity and expense of intravesical chemotherapy if it were accompanied by a commensurate reduction in disease progression or mortality. Unfortunately, continued maintenance chemotherapy appears to offer no advantage and perhaps even poses a disadvantage. All intravesical chemotherapeutic agents are active against DNA, that is, a rapidly dividing population of cells (tumor cells). Therefore, intravesical chemotherapy in the absence of tumor cells theoretically should not be beneficial. Thus, the concept of preventing urothelial tumor recurrence with intravesical cytotoxic chemotherapy is illogical unless one assumes the presence of occult malignancy.

Intravesical Immunotherapy: BCG Immunotherapy

Mechanism of Action
The live, attenuated tuberculosis vaccine, BCG, was noted to have potential antineoplastic effect by Pearl in 1929, but it was not until 1976 that Morales and associates[28] first reported the use of intravesical BCG in the management of early-stage bladder cancer. BCG is a nonspecific, immune-system stimulant. Intravesical instillation results in an inflammatory cell infiltrate. BCG activates macrophages, T cells, B cells, natural killer cells, and killer cells.[29] It is known to stimulate lymphokine and interferon production, which is thought to enhance natural killer cell activity.[30-32] BCG produces a T cell-mediated response linked to antitumor activity in both humans and mice.[33] After intravesical instillation, live mycobacteria attach to the urothelial lining; this process is facilitated by fibronectin, a component of the extracellular matrix. BCG organisms are then internalized by bladder epithelial cells,[34,35] leaving bacterial cell surface glycoproteins attached to epithelial cell membranes. This antigen is thought to mediate the immune response.[36] BCG also inhibits tumor cell motility through a mechanism involving the BCG-fibronectin-tumor cell interaction.[37]

Efficacy of BCG
Currently, BCG is the most effective intravesical agent for the treatment and prophylaxis of superficial bladder cancer. It also prevents bladder tumor recurrence and progression, increases the disease-free interval, and prolongs survival. In 6 of 6 prospective, controlled studies, there was an average 44% reduction in tumor recurrence.[14] Long-term follow-up studies have consistently demonstrated prolonged protection from tumor recurrence following BCG. Table I summarizes 6 clinical studies comparing surgery alone with intravesical BCG immunotherapy, all demonstrating the advantage of BCG treatment.[38-43]
Herr and associates[44] evaluated 86 patients and reported that stage progression occurred in 35% of controls and in 28% of patients treated with BCG. If the definition of progression is expanded to include those patients requiring multiple resections and alternative therapy, then progression occurred in 95% of controls and 53% of those treated with BCG. The mortality rate was reduced from 32% to 14% with BCG use, and cystectomy was required in 42% of controls versus 26% with BCG treatment. In a subsequent report with 3 years additional follow-up, cancer deaths were reduced from 37% to 12% (P<0.01).[45] In 3 controlled studies, overall mean rate of progression was reduced from 28% in controls to 14% in those receiving BCG.
BCG is the only intravesical treatment indicated for CIS. Based on data from more than 1500 patients, the average complete response (CR) rate of CIS to BCG was greater than 70%.[11] CR rates for chemotherapy averaged less than 50%, and, in general, less than 20% of patients treated with chemotherapy remain disease-free long-term. In contrast, Lamm[14] reported that optimal BCG immunotherapy increased the complete response rate to 87% and maintained long-term disease-free status in 83% of patients. Importantly, early results suggest that the overall survival in patients with superficial bladder cancer associated with a single 6-week course of BCG immunotherapy of 86% can be further improved with maintenance BCG to 92% (P<0.04). Witjes and colleagues[46] confirmed the effectiveness of BCG in reducing tumor progression in high-risk patients who had failed prior intravesical chemotherapy for recurrent superficial TCC and subsequently underwent intravesical BCG therapy.
BCG immunotherapy reduces tumor recurrence by an average of 40%, versus 14% average reduction with chemotherapy.[14] The Southwest Oncology Group (SWOG)[13] reported that 32.6% of patients treated with mitomycin had tumor recurrence, versus 19.5% of BCG-treated patients. The median time to recurrence was prolonged up to 36 months for the BCG-treated group, versus 20 months for the mitomycin-treated group. In a series of 161 patients enrolled in a 3-arm study of intravesical prophylaxis of epirubicin versus BCG versus TUR alone, Melekos and associates[47] reported that 60% of epirubicin-treated patients, 68% of BCG-treated patients, and 41% of control subjects remained free of recurrences for a mean follow-up of 33 months. Epirubicin and BCG were superior to TUR alone. Cookson and Sarosdy[48] reported that 91% of patients treated with intravesical BCG immunotherapy were free of disease at a mean follow-up of 59 months.
Theoretical reasons have been proposed to explain the advantage of immunotherapy over chemotherapy in terms of long-term recurrence and disease progression. Because BCG vaccine produces a mucosal infection that can persist for many months, the continued replication of organisms provides a much longer duration of action than chemotherapy. Chemotherapeutic agents decrease in concentration rapidly after instillation and are removed with voiding 2 hours after instillation. Immunotherapy also has the potential to induce specific immunity to bladder tumors and to prevent de novo tumor recurrence. Finally, BCG is able to penetrate deep within the detrusor muscle and has even been observed in pelvic lymph nodes after instillation, while chemotherapy is dependent on simple diffusion and penetrates to the depths of tumor extension poorly.

BCG Treatment Schedules
The optimum dose and treatment schedule for intravesical BCG remain under investigation. Because the original treatment schedule of 6 weekly instillations reported by Morales and colleagues[28] in 1976 was highly effective, it has been difficult to prove the superiority of any other schedule. Current data suggest that an intravesical dose between 100 million (1x108) and 1 billion (1x1010) colony-forming units (CFU) is effective, but responses have been reported with doses as low as 10 million (1x107) CFU or 1mg BCG.[49] The dose-response curve of BCG is bell shaped; excess BCG can reduce antitumor activity and even produce enhanced tumor growth.
The effect of BCG is not immediate, but is the consequence of prior immune stimulation. Herr and associates[50] reported that 32% of patients who had disease at 3 months after a 6-week course of BCG were disease-free by 6 months. Catalona and coworkers[51] reported that 44% of 100 patients responded completely to a 6-week course of BCG, while the cumulative complete response was improved to 63% if nonresponders were treated with a second 6-week course of BCG. Haaff and associates[52] treated patients who did not respond to an initial 6-week course of BCG with an additional 6-week course of BCG; 43% to 67% became tumor-free after the additional therapy.
Based on data showing that a single 6-week course of BCG is suboptimal, most urologists have repeated the 6-week course of BCG for tumor recurrence. However, based on immunologic studies and the SWOG experience with maintenance BCG, we now consider the "6+6" BCG regimen to be a common mistake. The success of the "6+" regimen (63% to 67% tumor free) is far inferior to the "6+3" regimen proposed by Lamm and colleagues.[53] With administration of 3 weekly BCG treatments 6 weeks after completion of induction, 87% of patients with CIS had complete response and 83% of patients with CIS or rapidly recurring Ta, T1 TCC remained tumor-free.[53] Urinary cytokines peak in most patients after the initial sixth BCG instillation, but patients who have previously received BCG induction have optimal stimulation at 3 weeks. Continued weekly BCG administration for a second, fourth, fifth, and sixth weekly instillation suppresses immune response and increases toxicity. Many patients who have failed the "6+6" regimen may have received too much rather than too little BCG.
In order to improve further the efficacy of BCG, Lamm and colleagues[54] reported that daily megadose vitamins A, B6, C, and E versus recommended daily allowances (RDA) produced protection from recurrence and tumor progression. The 5-year estimates of tumor recurrence are 91% in the RDA and 41% in the megadose group. Overall recurrence was 24/30 (80%) patients in the RDA group and 14 of 35 (40%) in the high-dose arm. Tumor recurrence was reduced in all tumor grades and stages studied, but maximal benefit occurred in low-grade stage Ta tumors. These results suggest that high doses of vitamins A, B6, C, and E may have a role in chemoprevention of bladder tumor recurrence, but further research will be required to confirm this study and to identify which of these vitamins protect from tumor recurrence.

Complications of BCG Therapy
BCG is generally well tolerated, but severe adverse reactions can occur. Symptoms of cystitis occur in up to 90% of treated patients.[55] Dysuria, frequency, low-grade fever, and malaise usually develop after the third instillation. These responses are usually self-limited, lasting about 24 hours. Such symptoms are best viewed as anticipated responses of the immune stimulation, rather than as adverse reactions. Most patients respond to symptomatic treatment with anticholinergics, pyridium, or nonsteroidal anti-inflammatory medications.
Hematuria may occur in one third of patients. There is concern as to whether patients with hematuria are at increased risk for systemic absorption of BCG and whether additional therapy should be delayed, if possible, until gross hematuria resolves. If irritative bladder symptoms, malaise, and fever persist or progress, isoniazid 300mg daily should be given until symptoms resolve. Such treatment is then reinstituted the day before BCG instillation and is continued for 3 days. Prophylactic isoniazid is not indicated for asymptomatic patients, and has been shown to decrease the immune stimulation of intravesical BCG in animals.[56]
Significant reactions to intravesical BCG occur in only 5% of patients. Fever greater than 103°F (39.4°C) is the most common reaction, occurring in 3% of all patients.[55] The febrile period is usually limited to 48 hours or less. The main concern with fever is the inability to distinguish an uncomplicated febrile episode from the onset of systemic BCG infection or hypersensitivity sepsis. Patients in whom a high fever develops should therefore be hospitalized for observation and treated daily with isoniazid 300mg and rifampicin 600mg. BCG sepsis has been observed in approximately 0.4% of patients treated with intravesical BCG, and to date, 10 deaths have been attributed to intravesical BCG.[55] Fortunately, with increased awareness of the need to postpone BCG treatments in patients with recent resection, hematuria, traumatic catheterization, or cystitis, the incidence of sepsis appears to have decreased. Patients with sepsis typically present with high fever, shaking chills, and hypotension, and may develop confusion, disseminated intravascular coagulopathy, and respiratory failure. Because BCG sepsis is not distinguishable from gram-negative sepsis early on, the patient should be treated with daily broad-spectrum antibiotics (for potential gram-negative sepsis), isoniazid 300mg, rifampicin 600mg, and prednisolone 40mg (for possible BCG hypersensitivity).[57] The addition of prednisolone resulted in 100% survival in 5 patients.[58] Alternative therapy that can be added to isoniazid and rifampin includes cycloserine 250-500mg twice daily or ethambutol 1200mg daily. In patients with systemic BCG infection or sepsis, antibiotic treatment is continued for 3 to 6 months.
Granulomatous prostatitis after BCG therapy occurred in 0.9% of patients, although the incidence has been as high as 40% based on prostate biopsies and as high as 75% based on cystectomy specimens.[58] In most cases, prostatitis is asymptomatic and no treatment is necessary. Acute urinary retention can occur secondary to prostatitis. Antituberculosis therapy with isoniazid and rifampicin for 3 months is indicated.
Other adverse reactions of intravesical BCG therapy include hepatitis or pneumonitis, each in 0.7% of patients, arthritis and migratory arthralgia in 0.5%, skin rash in 0.3%, epididymitis/orchitis in 0.4%, ureteral obstruction in 0.3%, and bladder contracture in 0.2%.55 Isoniazid is indicated for treatment and prophylaxis in the presence of any of these reactions, and rifampicin should be added when pneumonitis, hepatitis, or epididymo-orchitis is present.

Other Immunotherapeutic Agents

Interferons
Interferons (IFN) are host-produced glycoproteins that act to mediate host immune responses including antiviral, antiproliferative, and immunoregulatory activities. Kostakopulos and colleagues[59] used IFN-alpha in prophylaxis and reported tumor recurrence in 63% of treated T1 patients at 12 months. Torti and coworkers[60] reported 25% complete remission (CR) in 16 patients with recurrent papillary TCC and 32% CR and 26% partial response (PR, defined as persistent positive cytology) in 19 patients with refractory carcinoma in situ. Glashan[61] reported that tumor response to IFN was dose-dependent; there was a 5% CR and 32% PR with a dose of 10 x 106 and 43% CR and 19% PR observed with a dose of 100 x 106. Adverse reactions following intravesical IFN-alpha therapy are relatively mild and include flulike symptoms of fever, chills, fatigue, and myalgias, which occur in 27% of patients.

Keyhole Limpet Hemocyanin
Keyhole limpet hemocyanin (KLH), a highly antigenic respiratory pigment of the mollusc Megathuria crenulata, is a nonspecific immune stimulator. Jurincic and associates[62] reported that KLH was more effective than mitomycin in preventing recurrent superficial TCC. Of 21 patients in the KLH group (mean follow-up, 20.7 months), 3 (14.2%) had recurrences versus 9 of 23 (39.1%) in the mitomycin group (mean follow-up, 18.3 months) (P<0.05). Flamm and coworkers[63] compared KLH to ethoglucid for prophylaxis in patients who failed intravesical chemotherapeutic agents and reported no difference in efficacy. Lamm and colleagues[64] reported a CR in 45% patients and PR in 21% patients treated with KLH for 6 weeks. The best responders were patients with CIS; 58% had CR. The advantage of KLH is its apparent lack of toxicity. Lamm and associates[65] reported that crude preparation of KLH (C-KLH) offered greater antitumor activity than the purified KLH compound.

Bropirimine
Bropirimine, an aryl pyrimidine, is a low-molecular-weight immunomodulator with broad-spectrum immunostimulatory activity. It is effective as therapy for TCC of the urothelium. The spectrum of activity includes induction of endogenous interferons, IL-1, and TNF. It also stimulates B-cell proliferation, NK cells, lymphokine-activated killer cells (LAK), and macrophage activity. Sarosdy and coworkers[66] reported a 52% CR in patients treated for residual disease. The best responders were those without prior intravesical therapy; of these, 70% had CR.

Photofrin-Mediated Photodynamic Therapy
Photodynamic therapy (PDT) involves intravenous administration of photosensitizers with subsequent in situ intravesical activation by use of whole bladder photo laser therapy (WBPDT). The photosensitizer currently used is Photofrin® (sodium porfimer) (QLT PhotoTherapeutics), which is a mixture of hematoporphyrin-derived oligomers. Selective tumor kill occurs when tissue containing the photosensitizers is irradiated with visible light. PDT has been evaluated in the treatment of recurrent superficial papillary TCC and refractory CIS, as well as in prophylaxis of recurrent superficial TCC.[67]
In studies involving a total of 51 patients, papillary TCC, including T1 disease, was eradicated in 41%, while another 39% demonstrated PR, following a single PDT treatment. Tumor size remained a factor; CR was observed only in tumors less than 2cm in diameter. In a multicenter, randomized trial involving 36 patients, preliminary findings on 24 patients indicate a reduction in recurrence from 83% to 33% (net benefit of 50%) with a single prophylactic PDT treatment following a complete bladder resection. The mean time to tumor recurrence increased from 3 to 13 months. Long-term data on prevention, recurrence, or progression are not available.
PDT treatment is also effective in managing refractory CIS. In 1 review, Nseyo[67] reported that a single PDT treatment produced CR in 88% of the patients and 25% experienced recurrence during a mean follow-up of 13 months. No disease progression, no cystectomies, and no disease-related mortality were seen in a total of 27 patients with recurrent TCC or CIS who underwent a single PDT treatment during 15- to 20-month follow-up.
The mechanisms of action of PDT include direct cytotoxicity via single oxygen and superoxide radicals, vascular endothelial damage, and local immune response resulting in intense local inflammation. Consequently, PDT treatment produces cystitis (post-PDT syndrome) with symptoms of urinary frequency, urgency, nocturia, suprapubic pain, and bladder spasm. These symptoms are dose-dependent and vary in intensity and duration. The most severe adverse reaction of PDT treatment is permanent bladder contracture, which has been reported in 10% of patients.[67] With proper patient education and selection, the problem of Photofrin®-induced skin photosensitivity has been minimal; however, solar isolation is required for up to 6 weeks after Photofrin® injection. Introduction of new photosensitizers[68] and simplification of whole bladder laser light delivery[67] may lead to wide clinical application of PDT "in the management of" bladder cancer.

Conclusion
BCG immunotherapy represents a major advance in the treatment of superficial bladder cancer. Controlled studies have demonstrated that it significantly reduces both the short- and long-term recurrence of bladder cancer, and controlled comparative studies have shown that BCG is clearly superior to treatment with thiotepa, adriamycin, or mitomycin C. Unlike intravesical chemotherapy, BCG significantly reduces disease progression and mortality. Maintenance BCG has improved the long-term protection from tumor recurrence in Ta and T1 patients dramatically. Recent evidence from our double-blind controlled trial suggests that results of BCG therapy can be even further improved. Using a combination of 40,000 units of vitamin A, 100mg vitamin B6, 2g vitamin C, and 400 units vitamin E, we have reduced tumor recurrence in BCG-treated patients by an additional 40%. We now recommend this preparation, called Oncovite® (Mission Pharmacae), to all of our patients with bladder tumor. Interferons, KLH, and PDT are under investigation for the management of TCC, and although the efficacy results are encouraging, further work in these areas is required.