Urologic Oncology: Seminars and Original Investigations 32 (2014) 1172–1177
Original article
Cost-effectiveness of neoadjuvant chemotherapy before radical cystectomy for muscle-invasive bladder cancer Scott M. Stevenson, M.D., Matthew R. Danzig, B.S., Rashed A. Ghandour, M.D., Christopher M. Deibert, M.D., M.P.H., G. Joel Decastro, M.D., M.P.H., Mitchell C. Benson, M.D., James M. McKiernan, M.D.* Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY Received 20 February 2014; received in revised form 30 April 2014; accepted 3 May 2014
Abstract Objectives: To determine the costs of treatment and the duration of survival, adjusted for quality of life, for patients with muscle-invasive bladder cancer treated with immediate radical cystectomy (RC) or with neoadjuvant chemotherapy (NAC) with intent for subsequent RC. Methods and materials: A retrospective review of our institutional review board–approved database identified patients with muscleinvasive bladder cancer treated at our institution from 2004 to 2011. Patients were divided into those receiving RC alone and those receiving NAC before planned RC. Patients who refused RC following NAC were included in an intention-to-treat analysis. Survival duration was converted to quality-adjusted life years (QALYs), and costs of treatment per QALY were determined. Results: A total of 119 patients (65.4%) received RC alone and 63 (34.6%) received NAC, 38 of whom proceeded to cystectomy as planned. Mean total costs were $42,890 and $52,429 for RC and NAC, respectively (P ¼ 0.005). The 5-year overall survival was 31.7% and 42.5% for the RC-only group and the NAC group, respectively (P ¼ 0.034). The 5-year overall survival measured in QALYs was 21.9% and 42.9% for the RC-only and the NAC groups, respectively (P ¼ 0.021). The increased cost for NAC was $5,840 per additional life year gained (95% CI: $1,772–$9,909) and $6,187 per additional QALY gained (95% CI: $1,877–$10,498). Conclusions: The use of NAC is associated with a significant increase in quality-adjusted survival. The additional cost per QALY gained is approximately $6,000. The cost-utility analysis of NAC compares favorably with other cancer-specific therapies. r 2014 Elsevier Inc. All rights reserved.
Keywords: Bladder cancer; Neoadjuvant therapy; Cystectomy; Quality of life; Cost-effectiveness
1. Introduction Bladder cancer is the most expensive diagnosis per patient lifetime among all cancers [1], with a total cost of $3.98 billion annually in the United States in 2010 [2]. The annual cost to treat muscle-invasive bladder cancer (MIBC), for which radical cystectomy (RC) is considered the standard of care, is 4 times greater than non–muscle-invasive disease annually [3]. However, individual treatment choices may vary based on patient preferences or comorbidities [4]. Alternatives in select cases include neoadjuvant chemotherapy (NAC) with or without definitive surgery, partial cystectomy, Corresponding author. Tel.: þ1-212-305-5526. E-mail address: [email protected] (J.M. McKiernan). *
http://dx.doi.org/10.1016/j.urolonc.2014.05.001 1078-1439/r 2014 Elsevier Inc. All rights reserved.
or trimodality therapy consisting of maximal transurethral resection (TUR) with radiation and chemotherapy. Each has varying rates of local or systemic disease progression and associated morbidity [5–8]. Also, different treatment strategies are associated with highly variable health-related quality-of-life outcomes [9]. In 2003, the Southwest Oncology Group randomized controlled trial reported that a NAC regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) before RC improved survival among patients with nonmetastatic MIBC [7]. Despite this, a recent National Cancer Database review found that NAC utilization among eligible US patients was only 20.9% in 2010 [10]. Although adding NAC to RC has been shown to improve survival, this may increase total treatment costs, and chemotherapy-related
S.M. Stevenson et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1172–1177
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complications are likely to affect patients' quality of life. Cost analyses do not generally influence treatment guidelines in the United States, and in fact, the Patient Protection and Affordable Care Act expressly prohibits the use of costeffectiveness thresholds for treatment recommendations [11,12]. However, such analyses are widely used in the medical literature and provide an important perspective on the costs and benefits of treatment options, particularly for the many countries and health systems in which such considerations are increasingly valued [13]. To our knowledge, no studies have compared the effect of surgical treatment of MIBC with and without NAC on cost and quality of life in a cost-utility analysis. Although it has been shown that NAC improves absolute survival, it is not known how NAC affects the cost of treatment and patients' quality-adjusted life years (QALYs). We sought to determine the relationship between cost and QALYs gained for patients with MIBC being treated by RC alone versus RC preceded by NAC.
hospital stay was obtained from the nationwide 2009 Healthcare Cost and Utilization Project [15]. National median inpatient admission costs were applied to patients undergoing RC, based on the Diagnosis-Related Group identifier associated with that procedure (653, 654, or 655) (Table 1). Hospital length of stay (LOS) and maximum Clavien score were used as surrogates to determine a patient's most likely Diagnosis-Related Group. Admissions were categorized as having no significant complications (LOS r 10 d, Clavien r 1), minor complications (LOS ¼ 10–20 d or Clavien ¼ 2–3a), or major complications (LOS 4 20 d or Clavien Z 3b). Additional costs from admissions for initial diagnosis, disease treatment, and surgical or chemotherapy complications were obtained from the 2009 Healthcare Cost and Utilization Project based on the admission's primary ICD-9-CM [15]. The most frequent ICD-9-CM codes were as follows: malignant
2. Materials and methods
Procedure
Table 1 Individual treatment costs Cost, $ a
A retrospective review of our institutional review board– approved urologic oncology database was performed. A total of 217 patients were identified who were diagnosed at our center from 2004 to 2011 with stage II or stage III bladder cancer (tumor invading muscle but not extending into pelvic or abdominal wall [T2-T4a], without evidence of nodal involvement [N0] or distant metastasis [M0]). Patients were either initially staged or restaged according to the American Joint Committee on Cancer guidelines for bladder cancer from 2009 [14]. Patients were included if treated with NAC or RC. Included chemotherapy patients received MVAC; gemcitabine and cisplatin (GC); or gemcitabine and carboplatin when cisplatin was contraindicated. Patients were excluded if they received an unknown or ineligible NAC regimen, were treated with partial cystectomy or transurethral procedures only, or were lost to follow-up immediately after diagnosis. RC was performed by 1 of 8 uro-oncologists at our institution. Based on final pathology, a subset of chemotherapy-naïve patients who received RC also received adjuvant chemotherapy, adding to the cost of management. Moreover, NAC patients who declined RC after achieving complete response to chemotherapy (cT0) were included in the NAC group as part of the intention-to-treat analysis. Treatment information was reviewed. Subsequent outpatient interventions and encounters as well as all subsequent hospitalizations either directly or indirectly related to their diagnosis of bladder cancer were also reviewed. 2.1. Cost After tallying the health care encounters each patient had related to MIBC care, cost estimates were derived for each encounter type. The hospital cost for RC and the associated
Neoadjuvant chemotherapy MVAC Gemcitabine with or without cisplatin/carboplatin
11,373 16,416
Radical cystectomy Without complications or comorbidities With minor complications or comorbidities With major complications or comorbidities
15,350 20,127 31,858
Adjuvant or salvage chemotherapyb MVAC Gemcitabine with or without cisplatin/carboplatin
11,373 16,416
TURBT/endoscopic procedures Additional hospitalizations Urologist clinic visits and fees Outpatient imaging CT head without contrast CT head with contrast CT chest without contrast CT chest with contrast CT abdomen and pelvis without contrast CT abdomen and pelvis with contrast CT lower extremity CT-guided biopsy Ventilation-perfusion scan Bone scan PET scan with CT (whole body) MR head MR abdomen MR pelvis MR spine Renal scan Cystogram
1,143 c d
329 254 584 266 703 409 277 687 821 405 1,222 1,125 726 967 1,210 517 332
CT ¼ computed tomography; MR ¼ magnetic resonance; PET ¼ positron emission tomography; TURBT ¼ TUR of bladder tumor. a Includes pharmacy cost, supplemental medications, administration, oncologist visit, and fees. b Estimation based on neoadjuvant costs. c Too numerous to list here in full, based on admission ICD-9-CM. d Obtained individually for each patient from billing department.
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neoplasm of the bladder (188.8 and 188.9), urinary tract infection (599.0), surgical complication (997.4 and 997.5), ureteral obstruction (593.4 and 591), septicemia (038.9), neutropenia (288.00), and acute renal failure (584.9). Charges for outpatient imaging and procedures performed at our institution, such as outpatient cystoscopy and biopsy and surveillance computed tomography, bone, and positron emission tomography scans, were obtained from the accounting and billing departments and multiplied by the number of occurrences (Table 1). Outpatient charges for individual physician visits were obtained directly from our institution's billing department. To maintain uniformity in our cost analysis, a standard cost-to-charge ratio was applied for an urban hospital in New York State of 0.347 [16]. Total chemotherapy costs were estimated from published international sources for standard administrations and cycles of GC and MVAC in the neoadjuvant, adjuvant, and salvage settings, in locally advanced bladder cancer [17], owing to lack of similar published data from the United States. All cost figures used in our calculations are contemporary to our cohort's timeline between 2004 and 2011. Those figures not in US dollars were converted using an exchange rate at the time of the referenced study.
2.2. Utility A standard utility weighting system was used to calculate survival in terms of QALYs. QALYs represented a patient's overall duration of survival adjusted to reflect the undesirability of living in various states of suboptimal health. Utilities represent a quantification of this quality-of-life adjustment, with perfect health assigned a value of 1.0, and death equal to 0 [18–20]. Thus, a theoretical patient who lives for 8 years in a state of health whose utility is 1.0 has a survival in QALYs of 8, whereas living for 8 years in a state of health whose utility is 0.5 yields a survival in QALYs of 4 [21]. Major events and complications experienced by our study cohort were assigned a standard literature-based utility on this 0 to 1.0 scale (Table 2). Because of scarcity of literature about quality of life in patients with bladder cancer, some of the utilities used were extrapolated from studies involving patients with similar conditions and complications. Each treatment-related intervention or complication was assigned a standard length of time. Percentages of 2 common outcomes in RC patients, impotence and incontinence, were estimated based on published literature [22] owing to a lack of quality information on these outcomes in our patient records. All utilities were converted to a disutility (1—utility). Disutilities were multiplied by the time each patient spent in that health state (Table 2) or until the patient died, whichever came first. The negative utilities were then subtracted from patients' overall followup or survival to calculate QALYs. These methods have been described in further detail by Naglie et al. [23].
Table 2 Quality-of-life utilities Duration, d Utility Disease states Cystectomy (short term) Postcystectomy (urinary diversion) state TURBT Chemotherapy Disease recurrence or progression
60 a
7 103 b
Complications Prolonged ileus 7 Small bowel obstruction with conservative 7 management Small bowel obstruction with surgical intervention 30 Total peripheral nutrition 14 Atrial fibrillation/arrhythmia 7 Delirium 7 Urinary tract infection 7 Fluid collection/abscess with conservative 7 management Fluid collection/abscess with surgical intervention 30 Fever NOS 7 Pneumonia 30 Urinary obstruction requiring PCN or stent 90 DVT 180 PE 180 a Impotence a Incontinence Neutropenia 30 Acute illness (cellulitis, line infection, and wound 30 infection) Severe illness and hospitalization (bacteremia, 30 endocarditis, osteomyelitis, and septic shock) Acute sepsis 30 Kidney infections 30 b Urinary or fecal fistula a Death
0.80 0.96 0.90 0.64 0.62 0.65 0.65 0.55 0.65 0.99 0.51 0.73 0.64 0.64 0.64 0.85 0.75 0.67 0.62 0.90 0.76 0.64 0.64 0.53 0.47 0.66 0.68 0
DVT ¼ deep vein thrombosis; NOS ¼ not otherwise specified; PCN ¼ percutaneous nephrostomy tube; PE ¼ pulmonary embolism; TURBT ¼ TUR of bladder tumor. References for all utilities can be obtained by contacting the authors. a Permanent. b Until treatment or death.
2.3. Statistics Differences in mean total cost between study groups were analyzed using an independent variable t test. Survival was calculated from date of MIBC diagnosis. Overall survival (OS) as well as quality-adjusted OS (survival measured in QALYs) was assessed using Kaplan-Meier analyses and compared between groups using the stratified log-rank test. Two-tailed P values were used, with statistical significance set at r0.05. We then calculated the ratio of cost per QALY of quality-adjusted survival using the following formula: (Mean cost of treatment for NAC cohortMean cost of treatment for RC cohort)/(Median survival for NAC cohortMedian survival for RC cohort) The ratios derived by this method were compared between groups using an independent variable t test.
S.M. Stevenson et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1172–1177
Subgroup analyses were performed on NAC patients. Differences in survival and cost for those who received NAC with an RC compared with those who received NAC alone were calculated. Statistical analysis was performed using SPSS software version 19 (IBM Corp, Armonk, NY). 3. Results A total of 182 patients with MIBC were included. Overall, 119 (65.4%) patients received RC alone and 63 (34.6%) received NAC, with or without cystectomy. Baseline demographic information is presented in Table 3. Among the 63 patients receiving NAC, 38 (60.3%) subsequently proceeded to RC whereas 25 (39.7%) did not. Reasons for declining RC included patient preference after post-NAC restaging TUR demonstrated cT0 disease (13/25), or worsening clinical status that precluded surgery (12/25). In addition, 32 patients (51%) received a NAC regimen of MVAC, 26 (41%) received GC, and 5 (8%) received gemcitabine and carboplatin. Overall, 63 patients (52.9%) in the RC-only group and 27 patients (42.9%) in the NAC group died during the follow-up period. Median survival for the RC group and the NAC group was 26.6 months and 46.2 months, respectively (P ¼ 0.027). The 5-year OS was 31.7% and 42.5%, respectively (P ¼ 0.034). When adjusted for quality of life, median survival in QALYs for the RC group and the NAC group were 21.9 and 40.4 months, respectively (P ¼ 0.029) (Table 4). The Fig. displays the Kaplan-Meier analysis of OS measured in QALYs. The 5-year OS measured in QALYs was 21.9% and 42.9% for the RConly and the NAC groups, respectively (P ¼ 0.021). The mean total cost (range) for patients undergoing RC and NAC was $42,890 ($17,542–$142,708) and $52,429 ($17,396–$106,920), respectively (Table 4). The mean increased cost of care per patient in the NAC group
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Table 4 Survival and summary of costs Radical cystectomy n Median follow-up, mo Percentage who died during follow-up Median survival, mo Unadjusted QALY 5-Y overall survival Unadjusted QALY Mean total cost Percentage of total Radical cystectomy Early surgical complications Related hospital admissions Neoadjuvant chemotherapy Outpatient visits/procedures Adjuvant/salvage chemotherapy
Neoadjuvant P value chemotherapy
119 (65.4%) 63 (34.6%) 22.3 29.6 52.9% 42.9%
26.6 21.9
46.2 40.4
0.027 0.029
31.7% 21.9%
42.5% 42.9%
0.034 0.021
$42,890
$52,429
0.005
35.8 11.8 22.9 0 20.6 8.9
17.7 3.0 24.3 26.2 26.4 1.7
compared with the RC group was $9,539 (95% CI: $2,894–$16,184, P ¼ 0.005). The increased costs for NAC per additional life year gained and per additional
Table 3 Baseline demographics
n Mean age, y Percentage of men Race White Black Asian Hispanic Other Clinical stage T2 T3 T4
Radical cystectomy
Neoadjuvant chemotherapy
119 (65%) 72.5 72.3
63 (35%) 68.0 69.8
0.004 0.73
49 3 2 0 9
(77.8%) (4.8%) (3.2%) (0%) (14.3%)
0.30 0.21 0.80 0.04 0.40
52 (82.5%) 9 (14.3%) 2 (3.2%)
0.86 0.51 0.24
84 12 3 8 12
(70.6%) (10.1%) (2.5%) (6.7%) (10.1%)
97 (81.5%) 13 (10.9%) 9 (7.6%)
P value
Fig. Kaplan-Meier analysis of overall survival, in QALYs.
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QALY were $5,840 (95% CI: $1,772–$9,909) and $6,187 (95% CI: $1,877–$10,498), respectively, or approximately $17 per day. Within the NAC group, 38 of 63 patients (60.3%) received RC and 25 of 63 (39.7%) did not. The 5-year OS for those who received an RC and those who did not was 29.7% and 63.9%, respectively (P ¼ 0.097), and the 5-year OS in QALYs was 31.7% and 63.3%, respectively (P ¼ 0.105). The mean cost of treatment for those who received RC and those who did not was $58,177 and $43,693, respectively, with a difference of $14,484 (95% CI: $4,599–$24,369, P ¼ 0.005).
4. Discussion Our main findings are that in this cohort of patients with MIBC, NAC is cost-effective with an additional cost per QALY gained of $6,187. This compares favorably with other well-accepted cancer treatments in that it is less expensive per QALY gained. For example, the incremental cost-effectiveness ratio (cost/QALY gained) of bicalutamide for men with metastatic prostate cancer is $33,677/QALY [24], that of trastuzumab for metastatic breast cancer is $145,000/QALY [25,26], and that of erlotinib for advanced pancreatic cancer is estimated between $400,000 and $500,000 per QALY gained [25,27]. In England's National Health Service, therapies are deemed cost-effective and available for general use if they are less than $50,000/ QALY, as determined by the National Institute for Health and Clinical Excellence [13]. In the United States, the use of cost-effectiveness thresholds to make recommendations of care is prohibited; however, the low cost per QALY gained by receiving NAC is an endorsement of its use as an efficient and effective intervention to extend and improve life [11,12]. Others have previously reported the total treatment cost for patients with bladder cancer. Avritscher et al. [28] reported a cost for their cohort of patients with all stages of bladder cancer of $65,158, which is slightly higher than our RC and NAC MIBC-limited cohort costs of $42,890 and $52,429, respectively. Additionally, our cost calculations used many literature-based estimations and may have missed some of the minor costs associated with treatment or complications. Although this may distort our total costs relative to other published studies, our internal consistency in methodology allows for meaningful comparison between treatment groups. We included those patients who received NAC but not subsequent RC on an intention-to-treat basis as part of the NAC group. At our institution, bladder preservation is offered to patients who obtain a complete clinical response (cT0) to NAC and who are not desirous of RC. These patients likely lowered the mean total cost for the NAC group as they did not incur the cost of RC. Additionally, they may have increased the QALY survival for the NAC
group as they did not experience the side effects and deterioration of quality of life associated with RC. It is interesting to note that our subgroup of patients who received NAC but not RC had the greatest 5-year OS and QALY survival among any group at 63.9% and 63.3%, respectively. This is consistent with reports of higher survival in the Southwest Oncology Group trial, where a 5-year survival of 85% was noted following NAC and pT0 status at the time of cystectomy [7]. Although good survival and QALY outcomes were associated with complete NAC response in the present study, it was not designed or powered in such a way as to allow comment on chemotherapy clinical response rates or their correlation with pathologic findings. We did not perform any multivariate analyses to validate the significance of survival differences seen between our cohorts, as level 1 evidence already exists for the survival benefit of NAC [7]. This study is limited by its retrospective design and because its cohort was selected from a single tertiary care institution. We were unable to obtain details on how patients were selected for receipt of NAC versus immediate cystectomy, creating a potential for selection bias. At our institution, all patients who undergo NAC receive consultations with a medical oncologist before initiating treatment; however, the percentage of those in the immediate RC group who consulted with a medical oncologist but declined NAC is unavailable. There were small but statistically significant differences between our 2 cohorts in the demographic variables of age and racial distribution. Furthermore, we are unable to accurately comment on which patients in either group had early T2 disease that may have been completely resected by TUR of bladder tumor before the initiation of definitive treatment; however, the percentage of overall T2 disease in each group was the same. Lastly, some of the costs were estimated from published sources rather than our institution's billing department, and chemotherapy regimen costs were derived from international estimates owing to unavailability of US data, both of which may limit the accuracy of the total costs determined. However, because these estimations were used uniformly throughout the study, they are unlikely to greatly influence the differences observed among groups.
5. Conclusion NAC use is associated with a significant increase in OS and quality-adjusted survival. The additional cost per QALY gained by the use of NAC is approximately $6,000. This compares favorably with other cancerspecific therapies. Treatment with NAC before a planned RC in MIBC is a cost-effective measure to extend and improve quality of life. Our findings may be particularly salient in countries and health systems in which treatment guidelines are more heavily influenced by calculations of cost per QALY gained.
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Original article
Cost-effectiveness of neoadjuvant chemotherapy before radical cystectomy for muscle-invasive bladder cancer Scott M. Stevenson, M.D., Matthew R. Danzig, B.S., Rashed A. Ghandour, M.D., Christopher M. Deibert, M.D., M.P.H., G. Joel Decastro, M.D., M.P.H., Mitchell C. Benson, M.D., James M. McKiernan, M.D.* Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY Received 20 February 2014; received in revised form 30 April 2014; accepted 3 May 2014
Abstract Objectives: To determine the costs of treatment and the duration of survival, adjusted for quality of life, for patients with muscle-invasive bladder cancer treated with immediate radical cystectomy (RC) or with neoadjuvant chemotherapy (NAC) with intent for subsequent RC. Methods and materials: A retrospective review of our institutional review board–approved database identified patients with muscleinvasive bladder cancer treated at our institution from 2004 to 2011. Patients were divided into those receiving RC alone and those receiving NAC before planned RC. Patients who refused RC following NAC were included in an intention-to-treat analysis. Survival duration was converted to quality-adjusted life years (QALYs), and costs of treatment per QALY were determined. Results: A total of 119 patients (65.4%) received RC alone and 63 (34.6%) received NAC, 38 of whom proceeded to cystectomy as planned. Mean total costs were $42,890 and $52,429 for RC and NAC, respectively (P ¼ 0.005). The 5-year overall survival was 31.7% and 42.5% for the RC-only group and the NAC group, respectively (P ¼ 0.034). The 5-year overall survival measured in QALYs was 21.9% and 42.9% for the RC-only and the NAC groups, respectively (P ¼ 0.021). The increased cost for NAC was $5,840 per additional life year gained (95% CI: $1,772–$9,909) and $6,187 per additional QALY gained (95% CI: $1,877–$10,498). Conclusions: The use of NAC is associated with a significant increase in quality-adjusted survival. The additional cost per QALY gained is approximately $6,000. The cost-utility analysis of NAC compares favorably with other cancer-specific therapies. r 2014 Elsevier Inc. All rights reserved.
Keywords: Bladder cancer; Neoadjuvant therapy; Cystectomy; Quality of life; Cost-effectiveness
1. Introduction Bladder cancer is the most expensive diagnosis per patient lifetime among all cancers [1], with a total cost of $3.98 billion annually in the United States in 2010 [2]. The annual cost to treat muscle-invasive bladder cancer (MIBC), for which radical cystectomy (RC) is considered the standard of care, is 4 times greater than non–muscle-invasive disease annually [3]. However, individual treatment choices may vary based on patient preferences or comorbidities [4]. Alternatives in select cases include neoadjuvant chemotherapy (NAC) with or without definitive surgery, partial cystectomy, Corresponding author. Tel.: þ1-212-305-5526. E-mail address: [email protected] (J.M. McKiernan). *
http://dx.doi.org/10.1016/j.urolonc.2014.05.001 1078-1439/r 2014 Elsevier Inc. All rights reserved.
or trimodality therapy consisting of maximal transurethral resection (TUR) with radiation and chemotherapy. Each has varying rates of local or systemic disease progression and associated morbidity [5–8]. Also, different treatment strategies are associated with highly variable health-related quality-of-life outcomes [9]. In 2003, the Southwest Oncology Group randomized controlled trial reported that a NAC regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) before RC improved survival among patients with nonmetastatic MIBC [7]. Despite this, a recent National Cancer Database review found that NAC utilization among eligible US patients was only 20.9% in 2010 [10]. Although adding NAC to RC has been shown to improve survival, this may increase total treatment costs, and chemotherapy-related
S.M. Stevenson et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1172–1177
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complications are likely to affect patients' quality of life. Cost analyses do not generally influence treatment guidelines in the United States, and in fact, the Patient Protection and Affordable Care Act expressly prohibits the use of costeffectiveness thresholds for treatment recommendations [11,12]. However, such analyses are widely used in the medical literature and provide an important perspective on the costs and benefits of treatment options, particularly for the many countries and health systems in which such considerations are increasingly valued [13]. To our knowledge, no studies have compared the effect of surgical treatment of MIBC with and without NAC on cost and quality of life in a cost-utility analysis. Although it has been shown that NAC improves absolute survival, it is not known how NAC affects the cost of treatment and patients' quality-adjusted life years (QALYs). We sought to determine the relationship between cost and QALYs gained for patients with MIBC being treated by RC alone versus RC preceded by NAC.
hospital stay was obtained from the nationwide 2009 Healthcare Cost and Utilization Project [15]. National median inpatient admission costs were applied to patients undergoing RC, based on the Diagnosis-Related Group identifier associated with that procedure (653, 654, or 655) (Table 1). Hospital length of stay (LOS) and maximum Clavien score were used as surrogates to determine a patient's most likely Diagnosis-Related Group. Admissions were categorized as having no significant complications (LOS r 10 d, Clavien r 1), minor complications (LOS ¼ 10–20 d or Clavien ¼ 2–3a), or major complications (LOS 4 20 d or Clavien Z 3b). Additional costs from admissions for initial diagnosis, disease treatment, and surgical or chemotherapy complications were obtained from the 2009 Healthcare Cost and Utilization Project based on the admission's primary ICD-9-CM [15]. The most frequent ICD-9-CM codes were as follows: malignant
2. Materials and methods
Procedure
Table 1 Individual treatment costs Cost, $ a
A retrospective review of our institutional review board– approved urologic oncology database was performed. A total of 217 patients were identified who were diagnosed at our center from 2004 to 2011 with stage II or stage III bladder cancer (tumor invading muscle but not extending into pelvic or abdominal wall [T2-T4a], without evidence of nodal involvement [N0] or distant metastasis [M0]). Patients were either initially staged or restaged according to the American Joint Committee on Cancer guidelines for bladder cancer from 2009 [14]. Patients were included if treated with NAC or RC. Included chemotherapy patients received MVAC; gemcitabine and cisplatin (GC); or gemcitabine and carboplatin when cisplatin was contraindicated. Patients were excluded if they received an unknown or ineligible NAC regimen, were treated with partial cystectomy or transurethral procedures only, or were lost to follow-up immediately after diagnosis. RC was performed by 1 of 8 uro-oncologists at our institution. Based on final pathology, a subset of chemotherapy-naïve patients who received RC also received adjuvant chemotherapy, adding to the cost of management. Moreover, NAC patients who declined RC after achieving complete response to chemotherapy (cT0) were included in the NAC group as part of the intention-to-treat analysis. Treatment information was reviewed. Subsequent outpatient interventions and encounters as well as all subsequent hospitalizations either directly or indirectly related to their diagnosis of bladder cancer were also reviewed. 2.1. Cost After tallying the health care encounters each patient had related to MIBC care, cost estimates were derived for each encounter type. The hospital cost for RC and the associated
Neoadjuvant chemotherapy MVAC Gemcitabine with or without cisplatin/carboplatin
11,373 16,416
Radical cystectomy Without complications or comorbidities With minor complications or comorbidities With major complications or comorbidities
15,350 20,127 31,858
Adjuvant or salvage chemotherapyb MVAC Gemcitabine with or without cisplatin/carboplatin
11,373 16,416
TURBT/endoscopic procedures Additional hospitalizations Urologist clinic visits and fees Outpatient imaging CT head without contrast CT head with contrast CT chest without contrast CT chest with contrast CT abdomen and pelvis without contrast CT abdomen and pelvis with contrast CT lower extremity CT-guided biopsy Ventilation-perfusion scan Bone scan PET scan with CT (whole body) MR head MR abdomen MR pelvis MR spine Renal scan Cystogram
1,143 c d
329 254 584 266 703 409 277 687 821 405 1,222 1,125 726 967 1,210 517 332
CT ¼ computed tomography; MR ¼ magnetic resonance; PET ¼ positron emission tomography; TURBT ¼ TUR of bladder tumor. a Includes pharmacy cost, supplemental medications, administration, oncologist visit, and fees. b Estimation based on neoadjuvant costs. c Too numerous to list here in full, based on admission ICD-9-CM. d Obtained individually for each patient from billing department.
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neoplasm of the bladder (188.8 and 188.9), urinary tract infection (599.0), surgical complication (997.4 and 997.5), ureteral obstruction (593.4 and 591), septicemia (038.9), neutropenia (288.00), and acute renal failure (584.9). Charges for outpatient imaging and procedures performed at our institution, such as outpatient cystoscopy and biopsy and surveillance computed tomography, bone, and positron emission tomography scans, were obtained from the accounting and billing departments and multiplied by the number of occurrences (Table 1). Outpatient charges for individual physician visits were obtained directly from our institution's billing department. To maintain uniformity in our cost analysis, a standard cost-to-charge ratio was applied for an urban hospital in New York State of 0.347 [16]. Total chemotherapy costs were estimated from published international sources for standard administrations and cycles of GC and MVAC in the neoadjuvant, adjuvant, and salvage settings, in locally advanced bladder cancer [17], owing to lack of similar published data from the United States. All cost figures used in our calculations are contemporary to our cohort's timeline between 2004 and 2011. Those figures not in US dollars were converted using an exchange rate at the time of the referenced study.
2.2. Utility A standard utility weighting system was used to calculate survival in terms of QALYs. QALYs represented a patient's overall duration of survival adjusted to reflect the undesirability of living in various states of suboptimal health. Utilities represent a quantification of this quality-of-life adjustment, with perfect health assigned a value of 1.0, and death equal to 0 [18–20]. Thus, a theoretical patient who lives for 8 years in a state of health whose utility is 1.0 has a survival in QALYs of 8, whereas living for 8 years in a state of health whose utility is 0.5 yields a survival in QALYs of 4 [21]. Major events and complications experienced by our study cohort were assigned a standard literature-based utility on this 0 to 1.0 scale (Table 2). Because of scarcity of literature about quality of life in patients with bladder cancer, some of the utilities used were extrapolated from studies involving patients with similar conditions and complications. Each treatment-related intervention or complication was assigned a standard length of time. Percentages of 2 common outcomes in RC patients, impotence and incontinence, were estimated based on published literature [22] owing to a lack of quality information on these outcomes in our patient records. All utilities were converted to a disutility (1—utility). Disutilities were multiplied by the time each patient spent in that health state (Table 2) or until the patient died, whichever came first. The negative utilities were then subtracted from patients' overall followup or survival to calculate QALYs. These methods have been described in further detail by Naglie et al. [23].
Table 2 Quality-of-life utilities Duration, d Utility Disease states Cystectomy (short term) Postcystectomy (urinary diversion) state TURBT Chemotherapy Disease recurrence or progression
60 a
7 103 b
Complications Prolonged ileus 7 Small bowel obstruction with conservative 7 management Small bowel obstruction with surgical intervention 30 Total peripheral nutrition 14 Atrial fibrillation/arrhythmia 7 Delirium 7 Urinary tract infection 7 Fluid collection/abscess with conservative 7 management Fluid collection/abscess with surgical intervention 30 Fever NOS 7 Pneumonia 30 Urinary obstruction requiring PCN or stent 90 DVT 180 PE 180 a Impotence a Incontinence Neutropenia 30 Acute illness (cellulitis, line infection, and wound 30 infection) Severe illness and hospitalization (bacteremia, 30 endocarditis, osteomyelitis, and septic shock) Acute sepsis 30 Kidney infections 30 b Urinary or fecal fistula a Death
0.80 0.96 0.90 0.64 0.62 0.65 0.65 0.55 0.65 0.99 0.51 0.73 0.64 0.64 0.64 0.85 0.75 0.67 0.62 0.90 0.76 0.64 0.64 0.53 0.47 0.66 0.68 0
DVT ¼ deep vein thrombosis; NOS ¼ not otherwise specified; PCN ¼ percutaneous nephrostomy tube; PE ¼ pulmonary embolism; TURBT ¼ TUR of bladder tumor. References for all utilities can be obtained by contacting the authors. a Permanent. b Until treatment or death.
2.3. Statistics Differences in mean total cost between study groups were analyzed using an independent variable t test. Survival was calculated from date of MIBC diagnosis. Overall survival (OS) as well as quality-adjusted OS (survival measured in QALYs) was assessed using Kaplan-Meier analyses and compared between groups using the stratified log-rank test. Two-tailed P values were used, with statistical significance set at r0.05. We then calculated the ratio of cost per QALY of quality-adjusted survival using the following formula: (Mean cost of treatment for NAC cohortMean cost of treatment for RC cohort)/(Median survival for NAC cohortMedian survival for RC cohort) The ratios derived by this method were compared between groups using an independent variable t test.
S.M. Stevenson et al. / Urologic Oncology: Seminars and Original Investigations 32 (2014) 1172–1177
Subgroup analyses were performed on NAC patients. Differences in survival and cost for those who received NAC with an RC compared with those who received NAC alone were calculated. Statistical analysis was performed using SPSS software version 19 (IBM Corp, Armonk, NY). 3. Results A total of 182 patients with MIBC were included. Overall, 119 (65.4%) patients received RC alone and 63 (34.6%) received NAC, with or without cystectomy. Baseline demographic information is presented in Table 3. Among the 63 patients receiving NAC, 38 (60.3%) subsequently proceeded to RC whereas 25 (39.7%) did not. Reasons for declining RC included patient preference after post-NAC restaging TUR demonstrated cT0 disease (13/25), or worsening clinical status that precluded surgery (12/25). In addition, 32 patients (51%) received a NAC regimen of MVAC, 26 (41%) received GC, and 5 (8%) received gemcitabine and carboplatin. Overall, 63 patients (52.9%) in the RC-only group and 27 patients (42.9%) in the NAC group died during the follow-up period. Median survival for the RC group and the NAC group was 26.6 months and 46.2 months, respectively (P ¼ 0.027). The 5-year OS was 31.7% and 42.5%, respectively (P ¼ 0.034). When adjusted for quality of life, median survival in QALYs for the RC group and the NAC group were 21.9 and 40.4 months, respectively (P ¼ 0.029) (Table 4). The Fig. displays the Kaplan-Meier analysis of OS measured in QALYs. The 5-year OS measured in QALYs was 21.9% and 42.9% for the RConly and the NAC groups, respectively (P ¼ 0.021). The mean total cost (range) for patients undergoing RC and NAC was $42,890 ($17,542–$142,708) and $52,429 ($17,396–$106,920), respectively (Table 4). The mean increased cost of care per patient in the NAC group
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Table 4 Survival and summary of costs Radical cystectomy n Median follow-up, mo Percentage who died during follow-up Median survival, mo Unadjusted QALY 5-Y overall survival Unadjusted QALY Mean total cost Percentage of total Radical cystectomy Early surgical complications Related hospital admissions Neoadjuvant chemotherapy Outpatient visits/procedures Adjuvant/salvage chemotherapy
Neoadjuvant P value chemotherapy
119 (65.4%) 63 (34.6%) 22.3 29.6 52.9% 42.9%
26.6 21.9
46.2 40.4
0.027 0.029
31.7% 21.9%
42.5% 42.9%
0.034 0.021
$42,890
$52,429
0.005
35.8 11.8 22.9 0 20.6 8.9
17.7 3.0 24.3 26.2 26.4 1.7
compared with the RC group was $9,539 (95% CI: $2,894–$16,184, P ¼ 0.005). The increased costs for NAC per additional life year gained and per additional
Table 3 Baseline demographics
n Mean age, y Percentage of men Race White Black Asian Hispanic Other Clinical stage T2 T3 T4
Radical cystectomy
Neoadjuvant chemotherapy
119 (65%) 72.5 72.3
63 (35%) 68.0 69.8
0.004 0.73
49 3 2 0 9
(77.8%) (4.8%) (3.2%) (0%) (14.3%)
0.30 0.21 0.80 0.04 0.40
52 (82.5%) 9 (14.3%) 2 (3.2%)
0.86 0.51 0.24
84 12 3 8 12
(70.6%) (10.1%) (2.5%) (6.7%) (10.1%)
97 (81.5%) 13 (10.9%) 9 (7.6%)
P value
Fig. Kaplan-Meier analysis of overall survival, in QALYs.
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QALY were $5,840 (95% CI: $1,772–$9,909) and $6,187 (95% CI: $1,877–$10,498), respectively, or approximately $17 per day. Within the NAC group, 38 of 63 patients (60.3%) received RC and 25 of 63 (39.7%) did not. The 5-year OS for those who received an RC and those who did not was 29.7% and 63.9%, respectively (P ¼ 0.097), and the 5-year OS in QALYs was 31.7% and 63.3%, respectively (P ¼ 0.105). The mean cost of treatment for those who received RC and those who did not was $58,177 and $43,693, respectively, with a difference of $14,484 (95% CI: $4,599–$24,369, P ¼ 0.005).
4. Discussion Our main findings are that in this cohort of patients with MIBC, NAC is cost-effective with an additional cost per QALY gained of $6,187. This compares favorably with other well-accepted cancer treatments in that it is less expensive per QALY gained. For example, the incremental cost-effectiveness ratio (cost/QALY gained) of bicalutamide for men with metastatic prostate cancer is $33,677/QALY [24], that of trastuzumab for metastatic breast cancer is $145,000/QALY [25,26], and that of erlotinib for advanced pancreatic cancer is estimated between $400,000 and $500,000 per QALY gained [25,27]. In England's National Health Service, therapies are deemed cost-effective and available for general use if they are less than $50,000/ QALY, as determined by the National Institute for Health and Clinical Excellence [13]. In the United States, the use of cost-effectiveness thresholds to make recommendations of care is prohibited; however, the low cost per QALY gained by receiving NAC is an endorsement of its use as an efficient and effective intervention to extend and improve life [11,12]. Others have previously reported the total treatment cost for patients with bladder cancer. Avritscher et al. [28] reported a cost for their cohort of patients with all stages of bladder cancer of $65,158, which is slightly higher than our RC and NAC MIBC-limited cohort costs of $42,890 and $52,429, respectively. Additionally, our cost calculations used many literature-based estimations and may have missed some of the minor costs associated with treatment or complications. Although this may distort our total costs relative to other published studies, our internal consistency in methodology allows for meaningful comparison between treatment groups. We included those patients who received NAC but not subsequent RC on an intention-to-treat basis as part of the NAC group. At our institution, bladder preservation is offered to patients who obtain a complete clinical response (cT0) to NAC and who are not desirous of RC. These patients likely lowered the mean total cost for the NAC group as they did not incur the cost of RC. Additionally, they may have increased the QALY survival for the NAC
group as they did not experience the side effects and deterioration of quality of life associated with RC. It is interesting to note that our subgroup of patients who received NAC but not RC had the greatest 5-year OS and QALY survival among any group at 63.9% and 63.3%, respectively. This is consistent with reports of higher survival in the Southwest Oncology Group trial, where a 5-year survival of 85% was noted following NAC and pT0 status at the time of cystectomy [7]. Although good survival and QALY outcomes were associated with complete NAC response in the present study, it was not designed or powered in such a way as to allow comment on chemotherapy clinical response rates or their correlation with pathologic findings. We did not perform any multivariate analyses to validate the significance of survival differences seen between our cohorts, as level 1 evidence already exists for the survival benefit of NAC [7]. This study is limited by its retrospective design and because its cohort was selected from a single tertiary care institution. We were unable to obtain details on how patients were selected for receipt of NAC versus immediate cystectomy, creating a potential for selection bias. At our institution, all patients who undergo NAC receive consultations with a medical oncologist before initiating treatment; however, the percentage of those in the immediate RC group who consulted with a medical oncologist but declined NAC is unavailable. There were small but statistically significant differences between our 2 cohorts in the demographic variables of age and racial distribution. Furthermore, we are unable to accurately comment on which patients in either group had early T2 disease that may have been completely resected by TUR of bladder tumor before the initiation of definitive treatment; however, the percentage of overall T2 disease in each group was the same. Lastly, some of the costs were estimated from published sources rather than our institution's billing department, and chemotherapy regimen costs were derived from international estimates owing to unavailability of US data, both of which may limit the accuracy of the total costs determined. However, because these estimations were used uniformly throughout the study, they are unlikely to greatly influence the differences observed among groups.
5. Conclusion NAC use is associated with a significant increase in OS and quality-adjusted survival. The additional cost per QALY gained by the use of NAC is approximately $6,000. This compares favorably with other cancerspecific therapies. Treatment with NAC before a planned RC in MIBC is a cost-effective measure to extend and improve quality of life. Our findings may be particularly salient in countries and health systems in which treatment guidelines are more heavily influenced by calculations of cost per QALY gained.
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