CLINICAL THERAPEUTICS’IVOL. 22, NO. 4,200O Management of Patients with Bacilli Calmette-G&in-Refractory Carcinoma in Situ of the Urinary Bladder: Cost Implications of a Clinical Trial for Valruhicin Albert Marchetti, MD,’ Liping Wang, MS,’ Raf Magar,’ H. Barton Grossman, MD,2 Donald L. Lamm, MD,3 Paul F. Schellhammer, MD,4 and Paula Erwin-Toth, MSN, RN, CETNS ‘Health Economics Reseurch, Secaucus, New Jersey, 2Depurtment of Urology The University of Texas M.D. Anderson Cancer Center, Houston, Texus, -‘Department of Urology, West Virginia University School qf Medicine, Morgantown, West Virginiu, 4Department of Urology, Eustern Virginia Medical School, Senturu Cuncer Institute, Not-folk, Virginia, and 5Ckvelund Clinic Foundation, Cle~~eland, Ohio ABSTRACT Objective: This study was undertaken to identify the expected first- and second-year clinical costs associated with intravesical valrubicin therapy, using a decision analytic model, for patients with Bacilli Calmette-GuCrin (BCG)-refractory carcinoma in situ (CIS) of the urinary bladder. Background: Cancer of the urinary bladder is the fourth most common malignancy in men and the sixth most common noncutaneous carcinoma overall. One histopathologic stage of bladder cancer is CIS, for which BCG intravesical immunotherapy is the first- line therapy. Radical cystectomy has been recommended for patients with CIS who do not respond to or become refractory to therapy with BCG. Surgery, however, may not be appropriate for all patients, especially those who are ineligible for the lengthy procedure because of advanced age or comorbidities and those who prefer alternative nonsurgical management. For these groups, intravesical valrubicin therapy is a plausible alternative. Methods: Models were developed and populated with data from 1 open-label study of 90 patients, information from the medical literature, and input from clinical experts. The analysis was conducted from the payor perspective for direct costs only. Results: Our data indicate that first- and second-year expected costs for valrubicin ther- apy are $l9,9 I2 and $23,496, respectively. Expected cost for radical cystectomy was also evaluated, since some patients may have no other option if drug therapy fails. Conclusion: Our cost-consequence analysis and clinical data provide decision-makers with tools to aid in global budgetary projections of fractional and total expected health care Accepted for publication February 22, 2000. Printed in the USA. Reproduction in whole or part is not permitted 422 A. MARCHETTI ET AL. costs associated with the management of ClS is an aggressive malignancy with a BCG-refractory CIS of the urinary bladder. potential for swift progression and inva- Key words: radical cystectomy, valru- sion. Clinical studies have demonstrated bicin, intravesical therapy, carcinoma in that -40% of patients diagnosed with CIS situ, expected cost. (Clin Ther. 2000;22: have invasive disease at 5 years and 60% 422438) at 10 years.5,9 Between I5 and 21 years after diagnosis, mortality is 4O%.5,9 The presence of or risk for invasive carcinoma INTRODUCTION occurs in up to 83% of papillary bladder Carcinoma of the urinary bladder is the tumors associated with CIS.i”-‘* fourth most common cancer in men and Bacilli Calmette-Guerin (BCG) im- the sixth most common noncutaneous ma- munotherapy has been reported to be more lignancy among all Americans, accounting effective than intravesical chemotherapy for 4% of all neoplasms and an estimated in the treatment of patients with superfi- 12,100 deaths in 1999.’ Bladder cancer ex- cial bladder cancer.1”,14 The complete re- hibits a distinct male proclivity, with a sponse rates after initial BCG treatment male:female ratio of 2.6: 1.’ In addition to averaged 70% in 18 studies.i5 A second a possible hereditary predisposition,2A ad- durable response to a repeat course of BCG vanced age is a pivotal nonmodifiable risk occurred in 50% of patients who experi- factor; indeed, bladder malignancies are enced a durable complete response to the considered diseases of the seventh decade.5 first induction course.i6~i8 However, pa- Risks of bladder cancer increase among tients in whom 2 courses of BCG failed persons with certain environmental and oc- had low rates of response to a third course cupational exposures.2,4 and carried higher risks for the develop- Of the >50,000 cases of bladder can- ment of invasive or metastatic disease.‘b’8 cer diagnosed annually in the United When BCG fails to control disease and States,‘,5s” -75% are confined to the mu- the risk of progression increases, surgery cosa, submucosa, or lamina propria at pre- is appropriate. Radical cystectomy is an sentation.” According to the tumor-node- effective surgical intervention for patients metastasis staging system,j superficial with CIS who are refractory to BCG ther- bladder malignancies include Ta (nonin- apy. Five- and 1O-year cancer-specific sur- vasive papillary carcinoma), Tis (carci- vival rates of 290% have been docu- noma in situ [CIS]), and T, (invasion of mented.i9 The overall operative mortality the lamina propria). rate is -2.5%.‘9~20 Long-term postopera- Characterized morphologically as a flat tive complications occurred in 30% of the tumor, CIS consists of malignant cells that patients in 1 retrospective clinical study.*” do not extend into the bladder lumen or After cystectomy, conduit diversions that permeate the basement membrane into the require the use of external collecting ap- lamina propria.7 Consequently, it may be pliances are commonly performed. These more difficult to detect than papillary car- surgical procedures are associated with cin0ma.s In -20% of patients,” CIS pre- considerable physical and psychologic sents as a diffuse multifocal disease in- trauma that necessitate counseling and volving the ureters, prostatic urethra, and training predominantly related to enteros- prostatic ducts. tomal considerations.*’ 423 CLINICAL THERAPEUTICS” Although surgery is safe and effective rubicin therapy for patients with BCG- after BCG failure, it may not be appro- refractory CIS of the urinary bladder, a priate for some patients. For instance, the cost-analysis was conducted from the surgical mortality rate is higher in elderly payor perspective. patients (3% to 6%) than in younger pa- tients (1% to 3%).** In addition, elderly MATERIALS AND METHODS patients are prone to a number of chronic conditions (eg, cardiovascular or cere- Analytic Models brovascular diseases, clotting disorders, hypertension, arrhythmias, and concur- Based on the valrubicin clinical triaL2’ rent malignancy) that may complicate or which was supplemented with informa- contraindicate radical cystectomy.2” tion from the medical literature and ex- With the advent of valrubicin, a viable pert opinion, a model was developed to alternative to radical cystectomy has depict management pathways for patients emerged for patients who are poor surgi- with BCG-refractory CIS of the urinary cal candidates or who prefer medical bladder who received valrubicin treat- rather than surgical management. Valru- ment. The 5 expert clinicians who con- bicin is a cytotoxic anthracycline deriva- tributed to this effort have extensive tive that is structurally related to doxoru- knowledge of bladder cancer and broad bicin and has a similar mechanism of experience in the clinical management of action. It exhibits high tumor-cell pene- patients; they were independent of the tration and low absorption across the blad- study grantor. For these reasons, they were der wall.*” In an open-label clinical trial, asked to guide the clinical assessment and 90 patients with BCG-refractory CIS were development of the model. No conflict of treated with valrubicin at a dosage of 800 interest was identified before their partic- mg/wk for 6 weeks*‘; among patients who ipation. Advice was obtained in several had undergone 22 courses of intravesical ways without any weighting of geographic chemotherapy including 21 course of region for each advisor. BCG therapy, disease-free response rates Initially, advisors were informed of the to valrubicin therapy were 44% at 3 months nature of the research and asked if they and 2 1% at 6 monthsz5 were interested in contributing. Next, each Valrubicin has been licensed as “in- took part in a preliminary discussion to travesical therapy of BCG-refractory CIS identify issues of clinical and economic of the urinary bladder in patients for importance. A survey was then created whom immediate cystectomy would be and sent to the advisors to capture rele- associated with unacceptable morbidity vant data and information based on their or mortality.“24 As with any newly li- initial concerns. Finally, any discrepan- censed health care product, safety and ef- cies among the responses were resolved ficacy are primary concerns, but they are by telephone conversation. A final review not the only considerations that affect clin- was offered to each advisor. ical decisions. The cost of care is also fac- Through the process, a simulation model tored into the decision-making process. was developed to depict management path- To identify the expected first- and second- ways for patients whose BCG treatment year costs associated with intravesical val- failed. Such models provide an analytic 424 A. MARCHETTI ET AL. framework from which to estimate clinical tory procedures, and hospitalization, plus and economic consequences under uncer- the costs of management of adverse events tain conditions. Modeling and data analy- and therapeutic complications. Clinical