Bacillus calmete-guérin plus interferon-α2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity

Urologic Oncology: Seminars and Original Investigations 21 (2003) 354 –360

Original article

Bacillus Calmete-Gue´rin plus interferon-␣2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity John S. Lam, M.D.a, Mitchell C. Benson, M.D.a, Michael A. O’Donnell, M.D.b, Alexandra Sawczuk, B.S.N., R.N.c, Anna Gavazzi, B.S.N., R.N.a, Michael H. Wechsler, M.D.a, Ihor S. Sawczuk, M.D.a,c,* a

Department of Urology, Columbia University College of Physicians and Surgeons, New York, NY, USA b Department of Urology, University of Iowa College of Medicine, Iowa City, IA, USA c Department of Urology, Hackensack University Medical Center, Hackensack, NJ, USA Received 7 July 2002; received in revised form 25 October 2002; accepted 10 November 2002

Abstract Bacillus Calmette-Gue´rin (BCG) and interferon-␣2B (IFN-␣2B) have both been individually used for the intravesical treatment of superficial bladder cancer. We report our experience on the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-␣2B for treating superficial bladder cancer, including patients failing previous BCG therapy. Thirty-two patients with superficial bladder cancer underwent 6 weekly treatments with full-, one-third, or one-tenth-dose of BCG plus 50 or 100 MU of IFN-␣2B based on prior BCG exposure and tolerance. Patients with no evidence of disease proceeded onto maintenance therapy of 3 weekly treatments at 3 months followed by 2 additional maintenance cycles given 6 months apart. Response was assessed by cystoscopy/biopsy every 3 months after treatment. Before BCG plus IFN-␣2B treatment, 20 patients (63%) had previously failed intravesical BCG therapy, 27 (84%) had aggressive disease (stage T1, grade 3, or carcinoma in situ), 27 (84%) had recurrent disease, 14 (44%) had multifocal disease, and 6 (19%) had disease of over 4 years duration. At median follow-up of 22 months, 21 patients (66%) remain disease-free and 11 patients (34%) had disease-recurrence. Nineteen of 32 patients (59%) were disease-free after the initial induction cycle. Six of 11 patients 55% ultimately failing combination therapy did so at the first 3 to 4 month evaluation. Four of 7 patients (57%) benefited from salvage re-induction therapy. Of the 20 patients previously treated with BCG, 12 patients (60%) remain disease-free. Combination BCG plus IFN-␣2B intravesical therapy was well tolerated. Combination intravesical BCG plus IFN-␣2B is an effective and tolerable alternative for patients with superficial bladder cancer, including those patients in whom intravesical BCG therapy had previously failed. Benefits of this combination therapy may include potentially less morbidity, improved clinical efficacy, and in the long term, fewer patients undergoing radical therapy. However, radical treatment options should be pursued for early failures of this combination regimen in those patients with risk factors for recurrence and progression. © 2003 Elsevier Inc. All rights reserved. Keywords: Bacillus Calmette-Gue´rin; Interferon-␣2B; Bladder neoplasms; Therapeutics; Toxicity

1. Introduction Bladder cancer is the second most common urological malignancy in the United States with an estimated 56,500 new cases and 12,600 deaths to result from this disease in 2002 [1]. The majority of these tumors are transitional cell carcinoma (TCC) and are typically superficial (Ta, T1, or

* Corresponding author. Tel.: ⫹1-201-336-8090; fax: ⫹1-201-336-8221. E-mail address: [email protected] (I.S. Sawczuk). 1078-1439/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1078-1439(03)00012-7

Tis) [2]. The overall 10-year survival rate of patients with superficial disease is approximately 80%, but can range from 50% to greater than 95%, depending on the grade of the tumor [3,4]. The majority of TCCs will recur (40 – 80%) and approximately 20% of tumors diagnosed initially as superficial will progress to invade the muscle or become metastatic [5,6]. Complete transurethral resection of superficial disease followed by intravesical immunotherapy in patients deemed at risk for recurrence or progression can significantly improve outcome. The most efficacious adjuvant treatment of superficial

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bladder cancer involves successive instillation of the live mycobacterium bacillus Calmette-Gue´ rin (BCG) into the bladder. Intravesical therapy is commonly applied as adjuvant treatment to prophylax against recurrence and prevent progression, and as therapeutic treatment to eliminate residual small volume disease and carcinoma in situ (CIS). Immunotherapy with BCG has consistently resulted in initial complete response rates of 55 to 65% for papillary tumors and 70 to 75% for CIS [7,8]. Long-term studies have documented benefits in terms of decreased recurrence rate, decreased progression rate, reduced cystectomy rate, and even improved survival [9]. Despite good response rates, BCG treatments fail in 30 to 40% of cases and an additional 30 to 40% of initial responders relapse within 5 years [10 –12]. Furthermore, when this treatment fails, depending on the degree of bladder cancer aggressiveness, patients are faced with the prospects of repetitive surgical procedures, complete bladder removal, treatment with investigational intravesical agents or high-dose chemotherapy and radiation therapy. In addition, intravesical BCG therapy can be associated with significant toxicity, not permitting completion of optimal instillation schedules [13]. Intravesical instillation of recombinant interferon-␣2B (IFN-␣2B), while less effective than BCG as a monotherapy, has been shown to induce complete responses in up to 40% of patients with superficial bladder cancer, although its durability is limited with most relapsing within 1 year [14,15]. As a single agent, it has shown efficacy in cases of BCG failure and is associated with mild toxicity [16]. Recent studies have demonstrated that combination intravesical delivery of IFN-␣2B with reduced dose BCG for prior exposure or intolerance may demonstrate higher efficacy than either agent alone [17,18]. Combination therapy using IFN-␣ and full or reduced dose BCG may have a synergistic effect in patients with superficial bladder cancer, may rescue patients refractory to BCG, and reduce BCG toxicity [19,20]. This study assessed the therapeutic efficacy and toxicity of combination intravesical therapy with BCG plus IFN-␣2B for the treatment of patients with superficial bladder cancer, including those that had failed previous BCG therapy.

2. Materials and methods 2.1. Patients Between February 1999 and November 2001, patients with superficial bladder cancer, including those with relapse after previous BCG therapy or chemotherapy were enrolled into an Institutional Review Board (IRB) approved study at Columbia Presbyterian Medical Center, New York. Specifically included were patients with CIS, with or without papillary TCC tumors (Ta or T1); recurrent TCC grade 2 or 3; or extensive (defined as multifocal or solitary focus greater than 3 cm) TCC grade 2 or 3. At enrollment, informed consent was obtained, a medical history was taken, and physical examination was performed.

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Laboratory analyses (hematology, chemistry, and urinalysis), cytologic evaluation and cystoscopy (including random bladder biopsies) were performed for all patients. Mucosal biopsies included one or more biopsies of the lesion (s) and directed biopsies remote from the tumor (dome, right and left lateral walls, posterior bladder wall, and prostatic urethra), and from CIS lesions. Patients with muscle-invasive TCC, or TCC involving the upper tract, or prostatic urethra were excluded. 2.2. Schema Patients with superficial bladder cancer underwent one of three induction regimens based on prior BCG exposure and tolerance. Patients with no prior BCG treatment received 6 weekly treatments of standard full-dose Connaught strain BCG (81 mg) ⫹ 50 million units (MU) IFN-␣2B (Intron A, Schering-Plough Corporation, Kenilworth, NJ) mixed together in 50 mL of pyrogen-free water and instilled into the bladder by catheterization via gravity. The drug mixture was administered within 1 hour of reconstitution. Patients with prior BCG treatment who did not have to discontinue therapy because of intolerance received one-third dose of standard BCG ⫹ 50 MU IFN-␣2B administered intravesically once a week for 6 weeks. Patients that received prior BCG treatment and were BCG intolerance received weekly onetenth standard dose BCG ⫹ 100 MU IFN-␣2B for 6 weeks. If treatment intolerance occurred during induction, the patient received a 2-week rest followed by re-initiation of treatments at a BCG dose one-third of that of the prior dose, as well as premedication with urinary antispasmodics. Protocol design was based on prior studies reporting improved response with lower dose BCG therapy in patients previously sensitized with BCG [21], the independent single agent activity of at least 50 MU IFN-␣2B vs. 10 MU [14], and the recognized value of miniseries BCG maintenance therapy [22]. Rationale for BCG dose de-escalation or titration is because of dose-limiting toxicity of BCG therapy. Cystoscopy, biopsy and cytology were performed 4 to 6 weeks after completing the induction cycle. Patients that failed the induction cycle, but had no progression and evidence of improved aggressive features, or those that recurred with lower stage disease, underwent a salvage re-induction cycle that consisted of 6 weeks of one-tenth dose BCG plus 100 MU IFN-␣2B. Patients with no evidence of disease received their first standard maintenance cycle of 3 weekly treatments beginning 3 months from the end of induction. This consisted of one-third dose BCG plus 50 MU IFN-␣2B for dose 1 followed by two additional maintenance doses of one-tenth BCG plus 50 MU IFN-␣2B administered 6 months apart. Further dose decreases and intermittent 1 to 2 week delays in BCG administration were permitted when there was evidence of BCG intolerance, as defined by fever greater than 102°F less than 24 hours in duration, moderate to severe cystitis symptoms persisting beyond 3 days or inability to retain treatment at least 1 hour despite urinary antispasmodics, including narcotics. Clinical symptoms were monitored weekly during treatment and at

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3 and 6 months post-treatment. Treatment was concluded upon relapse with recurrent bladder cancer, progressive disease to stage T2 or higher; development of upper tract disease; or serious and recurrent adverse reaction to BCG or IFN-␣2B. 2.3. Response criteria Standard cystoscopic, biopsy of previous tumor sites, and cytologic evaluation were mandatory at 3-month intervals. Treatment success was defined as no evidence of disease (normal cystoscopic findings, negative cytology, and negative biopsies). Treatment failure was defined as a positive biopsy or positive cytology. Progression was defined as recurrence with higher pathological stage and/or grade disease, or the development of muscle-invasive disease or metastasis. Patients with treatment failure and no evidence of muscle-invasive disease underwent continued surveillance, bladder tumor resection, and additional intravesical therapy. For patients with CIS, treatment success was defined as complete resolution of CIS confirmed by negative biopsy and negative cytology. Recurrence of CIS proven on biopsy or positive cytology was designated as treatment failure. For patients with papillary TCC, treatment success was defined by normal appearance at cystoscopy with or without biopsies, and nonpositive urinary cytology. Tumor progression included treatment failure with progression to a higher pathologic stage, recurrence of pT1 tumor, progression to a higher histologic grade, recurrence of high grade TCC, or unresectable TCC. Median follow-up for the group overall was 22 months (mean 24, range 10 to 35). No patient was lost to follow-up. 2.4. Evaluation of toxicity Toxicity was evaluated through patient reports, observation by the investigators, and local and systemic reactions. A quantitative bladder symptom questionnaire was completed by each patient following each treatment and before cytoscopy. The severity of adverse reactions was graded according to World Health Organization (WHO) guidelines (grade 1, mild toxicity; grade 2, moderate toxicity; grade 3, severe toxicity; grade 4, life-threatening toxicity).

3. Results All patients had a confirmed diagnosis of bladder cancer. Patient demographics and risk factors for recurrence or progression before BCG plus IFN-␣2B treatment are shown in Table 1. Before treatment with intravesical BCG plus IFN-␣2B, 5 patients had nonaggressive tumors (Ta, grade 1–2) and 27 patients had aggressive tumors (T1, grade 3, or CIS alone or in combination). The stage/grade at diagnosis included 5 patients with Ta/G2; 11 patients with Ta (G1 ⫻ 2, G2 ⫻ 3, G3 ⫻ 6) and CIS; 2 patients with T1/G3; 7 patients with T1/G3 ⫹ CIS; and 7 patients with Tis. Con-

Table 1 Patient demographics and risk factors for recurrence and/or progression before combination BCG plus IFN-␣2B treatment Demographics/characteristics

No. Patients (%)

Prior intravesical BCG treatment Male Female Aggressive histology (stage T1, grade 3, CIS) Greater than 2 recurrences Prior intravesical chemotherapy Multiple/multifocal tumors Disease duration greater than 4 years BCG refractory with recurrence at less than 6 months BCG naive Male Female Aggressive histology (stage T1, grade 3, CIS) Greater than 2 recurrences Previous intravesical chemotherapy Multiple/multifocal tumors Disease duration greater than 4 years

20 (63%) 16 (50%) 4 (13%) 17 (53%) 12 (38%) 4 (13%) 8 (25%) 6 (19%) 11 (34%) 12 (37%) 10 (31%) 2 (6%) 10 (31%) 2 (6%) 1 (3%) 6 (19%) 0 (0%)

Key: BCG ⫽ bacillus Calmette-Gue´ rin; CIS ⫽ carcinoma in situ.

sidering CIS or any grade 3 disease, a total of 27 patients (84%) had high-grade disease. Of the 32 patients, 20 (63%) had failed previous intravesical BCG therapy, with 5 (16%) unable to tolerate standard BCG dosing. Eleven (34%) patients refractory to BCG therapy had disease recurrence at less than 6 months. Other disease characteristics present shown to cause a high risk of recurrence or progression included 14 (44%) patients that had greater than 2 recurrences, 14 (44%) that had multifocal disease, and 6 (19%) that had disease duration greater than 4 years. Overall, combination BCG plus IFN-␣2B therapy resulted in a 66% disease-free rate at median follow-up of 22 months, which included 12 of 20 (60%) patients previously treated with BCG and 9 of 12 (75%) BCG naive patients. Table 2 list responses by disease characteristics following treatment with the combination regimen of BCG plus IFN␣2B. There were no obvious differences in response according to stage, grade, or coexistent carcinoma in patients failing previous BCG therapy or those that were BCG naive. However, insufficient sample size and lack of strict comparison groups did not allow for meaningful statistical analysis. Following induction, 19 patients were tumor-free and 13 patients had a positive biopsy for an initial response rate of 59%. Of these 13 patients, 5 terminated treatment because of recurrence of T1 disease or worsening disease, 1 recurred (Ta/G3 ⫹ CIS), but without disease progression, and 7 underwent a salvage re-induction course for biopsypositive Ta disease with or without CIS, or Tis alone. Five patients terminating treatment proceeded onto radical cystectomy and currently remain alive and disease-free. Table 3 presents the final pathology for the cystectomy specimens of these 5 patients (no residual tumor, N0; pT1 ⫹ pTis, N0 ⫻ 2; pTis, N0; and pT2a ⫹ pTis, N1). Nineteen patients with no evidence of cancer after in-

J.S. Lam et al. / Urologic Oncology: Seminars and Original Investigations 21 (2003) 354 –360 Table 2 Breakdown by highest stage, grade, and coexistent CIS for patients treated with combination intravesical BCG plus IFN-␣2B at median follow-up of 22 months (range 10 to 35 months) Stage

radical cystectomy. Time to failure for these two patients was 12 and 21 months. The patient failing at 21 months had also undergone re-induction therapy with time to recurrence after re-induction at 12 months. Table 3 shows the final pathology for these 2 patients: pTa ⫹ pTis, N0 and no residual tumor, N0. Both patients currently remain alive with no evidence of disease. Of the 7 patients who underwent a salvage re-induction treatment (one-tenth BCG standard dose ⫹ 100 MU IFN-␣2B), 2 patients had a positive biopsy (Ta/G2 and Ta/G3) following re-induction. No disease progression was evident in the 2 patients failing reinduction. The 5 patients with a negative biopsy after reinduction proceeded onto maintenance therapy. One patient relapsed (Ta/G2) during maintenance therapy after responding to re-induction therapy with time to recurrence at 17 months after re-induction. Of the 20 patients previously treated with BCG, 8 (40%) failed at initial cystoscopic evaluation (3 months) and 12 (60%) proceeded onto maintenance therapy. One patient on maintenance therapy relapsed (Ta/G3 ⫹ CIS) and proceeded onto radical cystectomy (no residual tumor, N0). The stage/ grade at biopsy for the 8 patients previously treated with BCG and ultimately failing therapy included: 2 patients with Ta (G2 and G3); 3 patients with Ta/G3 ⫹ CIS; 1 patient with T1/G3; 1 patient with T1/G3 ⫹ CIS; and 1 patient with CIS alone. Of the 8 patients failing induction, 4 underwent a salvage reinduction cycle, of which 2 failed without disease progression and 2 responded and proceeded onto maintenance therapy. One patient on maintenance therapy relapsed (Ta/G2) after responding to re-induction therapy. Three patients with prior intravesical BCG therapy proceeded onto radical cystectomy (pT1 ⫹ pTis, N0 ⫻ 2; pT2a ⫹ pTis, N1). Similarly, 7 of 12 (58%) BCG naive patients responded

No. patients (% 22-mo. no evidence of disease)

Prior intravesical BCG treatment Ta: CIS No CIS T1 (grade): 3, CIS 3, no CIS Isolated CIS: With papillary TCC Any CIS Total: BCG naive Ta: CIS No CIS T1 (grade): 3, CIS 3, no CIS Isolated CIS: With papillary TCC Any CIS Total

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10 (50%) 7 (43%) 3 (67%) 4 (75%) 3 (100%) 1 (0%) 6 (67%) 10 (60%) 16 (63%) 20 (60%) 6 (83%) 4 (100%) 2 (50%) 5 (80%) 4 (75%) 1 (100%) 1 (0%) 8 (88%) 9 (78%) 12 (75%)

Key: BCG ⫽ bacillus Calmette-Gue´ rin; CIS ⫽ carcinoma in situ; TCC ⫽ transitional cell carcinoma.

duction therapy proceeded onto maintenance therapy (onethird BCG to one-tenth standard dose ⫹ 50 MU IFN-␣2B). Seventeen of 19 patients (89%) on maintenance therapy remain disease-free. Two patients on maintenance therapy relapsed with Ta/G3 ⫹ CIS disease and proceeded onto

Table 3 Summary of results for patients proceeding onto cystectomy following treatment with combination intravesical BCG plus IFN-␣2B with median time to failure of 3 months (range 3 to 15 months) Age (yr)/sex

Frequency of recurrence (pretreatment)

Tumor multiplicity/ multifocality

Stage/grade

Prior BCG treatment

Treatment dose*

Recurrence stage/grade

Time to failure (months)

Outcome and final pathology

64-F

⬎3/year

yes

Ta/G2

No

1

Ta/G3 ⫹ CIS

12

79-M

2–3/year

no

Ta/G2 ⫹ CIS

Yes

2

T1/G3

3

78-M

2 or less total

yes

T1/G3

Yes

2

T1/G3 ⫹ CIS

3

47-F

2 or less total

no

T1/G3 ⫹ CIS

No

1

T1/G3

3

78-M

2 or less total

yes

CIS

No

1

CIS

3

75-M

2–3/year

no

CIS

Yes

2† ⫹ R

Ta/G3 ⫹ CIS

21

78-M

2–3/year

no

CIS

Yes

2

Ta/G3 ⫹ CIS

3

Relapse/Progression-Cystectomy (pTa ⫹ pTis, N0; NED) Nonresponder/Progression-Cystectomy (pT1 ⫹ pTis, N0; NED) Nonresponder/Progression-Cystectomy (pT1 ⫹ pTis, N0; NED) Nonresponder/Progression-Cystectomy (no residual tumor, N0; NED) Nonresponder/Progression-Cystectomy (Tis, N0; NED) Relapse/Progression-Cystectomy (no residual tumor, N0; NED) Nonresponder/Progression-Cystectomy (pT2a ⫹ Tis, N1; NED)

* Dose 1 ⫽ Standard dose bacillus Calmette-Gue´ rin (BCG) ⫹ IFN-␣2B 50 million units (MU); 2 ⫽ 1/3 dose BCG ⫹ IFN-␣2B 50 MU; R (re-induction) ⫽ 1/10 dose BCG ⫹ IFN-␣2B 100 MU. † Prior intravesical chemotherapy.

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Table 4 Toxicities as a result of combination intravesical BCG plus IFN-␣2B treatment Symptoms

None

Mild

Moderate

Severe

Cystitis Hematuria Fever/chills Flu-like symptoms Arthralgia

0 (0%) 15 (47%) 16 (50%) 17 (53%) 23 (72%)

24 (75%) 14 (44%) 14 (44%) 11 (34%) 4 (13%)

7 (22%) 3 (9%) 1 (3%) 3 (9%) 4 (13%)

1 (3%) 0 (0%) 1 (3%) 1 (3%) 1 (3%)

following induction therapy and proceeded onto maintenance therapy. The stage/grade at biopsy for the 3 BCGnaive patients ultimately failing therapy included: 1 patient with Ta/G3 ⫹ CIS; 1 patient with T1/G3; and 1 patient with CIS alone. One patient on maintenance therapy relapsed (Ta/G3 ⫹ CIS) after responding to induction therapy and proceeded onto radical cystectomy (pTa ⫹ pTis, N0). Of the 5 patients failing induction therapy, 3 responded to salvage re-induction therapy and proceeded onto maintenance therapy and 2 patients proceeded onto radical cystectomy (no residual tumor, N0; pTis, N0). In total, 19 of 25 patients (86%) who had initially had CIS (alone or with pTCC) before combination BCG plus IFN-␣2B therapy, ultimately had no evidence of CIS following therapy. Of the 7 patients without CIS, 2 (27%) developed CIS after treatment. Toxicity observed was mild to moderate in severity (WHO grades 1 or 2) and occurred primarily on days of intravesical therapy. The side effects attributable to combined BCG plus IFN-␣2B were generally the same types associated with BCG therapy alone, including local cystitis, transient hematuria, fever, flu-like symptoms, and arthalgia. One patient had a severe clinical toxic event (WHO grade 3) because of BCG arthralgia and another patient had severe chills, fever, and cystitis; however, both were able to continue with treatment after appropriate BCG dose reduction or temporary treatment delay and have proceeded onto maintenance therapy. All toxic events resolved at the end of treatment with no sequelae noted at follow-up visits. The toxicity data is presented in Table 4. Cystitis was mild in 24 patients (75%), moderate in 7 patients (23%), and severe in 1 patient (3%). Hematuria was mild in 14 patients (44%) and moderate in 3 patients (10%). Fever or chills were mild in 14 patients (44%), moderate in 1 patient (3%), and severe in 1 patient (3%). Flu-like symptoms were mild in 11 patients (34%), moderate in 3 patients (10%), and severe in 1 patient (3%). Arthralgia was mild in 4 patients (13%), moderate in 4 patients (13%), and severe in 1 patient (3%) (Table 3). During salvage re-induction or maintenance therapy, symptoms did not intensify and were similar to that of during the first induction cycle. One patient had to delay therapy due to severe symptoms; however, this patient eventually completed induction therapy at a reduced dose of BCG and is currently disease-free and on maintenance therapy. All patients remaining on therapy have been able to tolerate treatments without adverse effects.

At a median follow-up of 22 months, 21/32 patients (66%) remain on maintenance therapy with no evidence of disease (NED). No patient was discontinued from therapy because of treatment intolerance including 5 patients that were previously deemed “intolerant” for repeat standard full-dose BCG. Thirteen patients failed initially after induction therapy, but 4 patients had a tumor-free response following re-induction therapy. Six of 11 patients (55%) ultimately failing combination therapy did so at the first 3 to 4 month evaluation after completion of induction. Eleven patients (34%) ultimately failed either initial induction or salvage re-induction treatment. The pathology at time of recurrence for those ultimately failing was as follows: 6 patients failing induction (Ta/G3 ⫹ CIS ⫻ 2; T1/G3 ⫹ CIS; T1/G3 ⫻ 2; CIS alone), 2 patients failing re-induction (Ta/G2-3 ⫻ 2), and 3 patients with disease recurrence (Ta/ G2; Ta/G3 ⫹ CIS ⫻ 2) while on maintenance therapy.

4. Discussion The most significant risk of superficial transitional cell carcinoma involving the urinary bladder is the capacity to progress into invasive and metastatic cancer [2,3]. CIS, stage T1, and grade 3 tumors carry the highest risk of disease progression [4,12]. The first line therapy for superficial tumors is transurethral resection, but the high rate of recurrence and multiplicity of tumors often renders surgical treatment alone insufficient. Adjuvant intravesical immunotherapy is most commonly indicated for grade 3 tumors, multifocal CIS, multiple recurrences, multiple tumors, large tumors, as well as T1 lesions [6]. BCG is recognized as the most potent intravesical agent in the treatment of superficial bladder cancer. It is effective in treating residual papillary disease, as well as CIS, and can be used as a prophylactic agent in recurrent superficial disease. The tumor-free response rates following an intravesical BCG treatment program are greater than 70% and there are significant long-term decreases in recurrence rates compared to transurethral resection alone [3,6]. In addition, tumor progression and mortality may also be reduced [4,5]. Despite the high efficacy of intravesical BCG immunotherapy, it is associated with dose-limiting toxicity, which includes dysuria, increased urinary frequency, hematuria with cystitis, and occasionally sepsis [13]. Given the substantial number of bladder cancer patients who experience recurrence or progression with current therapies and BCG associated toxicities, new less toxic approaches have been explored [23]. The dose-limiting toxicity of BCG therapy has led to the investigation of low-dose BCG for the treatment of superficial bladder cancer. With one exception, no significant differences were seen in either recurrence or progression rates for patients treated with either 27 or 81 mg of Connaught BCG [24]. This exception involved a single 6-week induction cycle of one-third BCG dose versus standard dose BCG in a North American cohort [25]. Elsewhere, low-dose

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Pasteur BCG (75 mg) has been shown to provide superior protection from recurrences and significantly lower toxicity compared to high doses of the vaccine, and an additional 6-week course achieved responses from patients who failed the induction course [21]. Maintenance therapy with lowdose Pasteur Paris BCG has been shown to produce a 75% complete response rate at 5-year follow-up in patients with stage T1 bladder cancer [26]. Quarter-dose BCG has also been shown to cause an ablative effect (61% response rate) on papillary marker lesions of the bladder, which is similar to the effect of full-dose BCG [27]. Interferons are endogeneous glycoproteins that mediate immune responses, having antiviral, antiproliferative, and immunoregulatory activities, and have been also shown to have antitumor activities [15]. Among several subtypes, IFN-␣2B has been the most extensively studied for bladder cancer. Interferon monotherapy can be effective in eradicating residual disease with complete responses of 20 to 43%. A multicenter randomized trial demonstrated a CIS response of 5% at low doses (10 MU) to as high as 43% at the high dose (100 MU) [14,28]. As a prophylactic agent following transurethral resection of bladder tumor, it demonstrates recurrence rates from 20 to 60% (mean 44%) [29]. Patients that fail BCG therapy for the first time can be retreated with BCG with a reasonable chance of success. However, patient tolerance to additional BCG treatments is often a problem, especially at the standard BCG dose. If the patient were to be able to tolerate another course of standard dose BCG, a third course has a success rate of less than 20% [30]. Interferon-␣ monotherapy has been used as salvage therapy and demonstrated success in a small percentage of patients (12%), but it is most effective for patients who have relapsed beyond 6 months [15,16]. Other conservative options for patients who have failed BCG therapy include intravesical chemotherapy regimens, such as valrubicin or mitomycin C, but the durable response rates at 2 years are 8 and 23%, respectively, and both of these agents are prone to causing cystitis [31,32]. Using combination low-dose BCG plus IFN-␣2B, a 55% complete response rate at 2.5 years has been demonstrated, and thus this may be a reasonable alternative for those patients failing BCG [19]. The primary aim of this study was to establish the therapeutic efficacy and toxicity of combination BCG plus IFN␣2B therapy in patients with confirmed superficial bladder cancer, including those that have failed previous intravesical therapy. BCG plus IFN-␣2B therapy was well tolerated at the doses investigated. Adverse effects were mild to moderate in severity in all patients, except for one and all adverse effects resolved after the end of treatment. All of our patients were able to complete the initial induction cycle. In addition, patients were able to tolerate a second salvage cycle and thus far, patients remaining on therapy have been able to tolerate maintenance cycles. Intravesical BCG immunotherapy produces local complications in 90% of patients and combination BCG plus IFN-␣2B therapy appears to be comparable to BCG alone in terms of tolerability [13]. These results suggest that combi-

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nation BCG plus IFN-␣2B therapy can safely be given to patients with bladder cancer. Important benefits of this new therapy may include potentially less morbidity (because of lower BCG dosing), improved clinical efficacy (including those that have failed prior therapy), and in the long term, fewer patients undergoing cystectomy. Although combination BCG plus IFN␣2B intravesical therapy appears promising, caution must be exercised when treating patients deemed at high-risk for progression of disease, such as those patients that have failed previous therapies and those with CIS and grade 3 tumors [24]. Our patients failing this combination regimen were able to proceed onto cystectomy and currently remain alive. Our results corroborate a recent study demonstrating that patients with BCG-refractory bladder cancers may benefit from combination BCG plus IFN-␣2B therapy without a significant risk of progression [33]. CIS occurs rarely in patients with well-differentiated, superficial bladder tumors, but is present in 25% or more of patients with high-grade superficial tumors [12]. It portends a poor prognosis and often progresses to muscle-invasive cancer. BCG remains the mainstay of treatment for CIS; however, many patients eventually fail BCG therapy. IFN-␣ monotherapy has also been shown to be efficacious for the treatment of CIS [28,29]. Of the 25 patients in our series that had CIS (alone or with TCC) before therapy, 19 (86%) had no evidence of CIS after treatment. Combination BCG plus IFN-␣2B therapy may be more efficacious and produce more complete responses to CIS than either therapy alone or it may be used salvage those that are BCG refractory. In our study, 12/20 patients (60%) who had failed prior BCG achieved a tumor-free response at median follow-up of 22 months, similar to that reported by O’Donnell et al. [19] who showed a 63% 12 month disease-free rate for an independent 40 patient cohort. The optimal management of superficial bladder cancer continues to be defined. Intravesical immunotherapy is the preferred therapy, unless the patient is severely immunocompromised. Although the “gold standard” treatment in this disease is intravesical BCG, recurrence rates of 20 to 50% and doselimiting toxicity suggest that alternatives are needed. The recurrence rate in our series was 34%, however, many of our patients are considered high-risk for disease progression and early recurrence. Twenty of our patients had failed previous BCG therapy and many had aggressive features associated with their bladder cancers. Early trials have suggested that combination regimens with BCG plus IFN-␣ appear to have additive or synergistic anti-tumor activity and may improve efficacy over BCG alone. Patients refractory to BCG have also been salvaged by this combination regimen. In addition, it may be possible to reduce BCG-associated morbidity without compromising efficacy by combining reduced doses of BCG with IFN-␣. While our median follow-up of 22 months in this study is admittedly short, our independent corroboration of findings from these previous studies lends strong support toward advo-

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cating this new treatment program, at least for higher risk patients.

5. Conclusions This present study of combination intravesical BCG plus IFN-␣2B therapy was conducted in 32 patients with confirmed superficial bladder cancer. This combination regimen appears to be an effective alternative for patients with superficial bladder cancer at high risk for recurrence or progression, including those patients that had failed previous intravesical BCG therapy. Significant toxicity with combination BCG plus IFN-␣2B therapy was not evident. Benefits of this combination therapy may include potentially less morbidity, improved clinical efficacy, and in the long term, fewer patients undergoing radical therapy.

Acknowledgments This study was supported in part by Integrated Therapeutics Group, Inc., Kenilworth, NJ.

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