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Surgical Recent Advances in Bladder Cancer

Bladder cancer is the most expensive cancer to treat from diagnosis to death. Frequent disease recurrence, intense follow-up, and expensive, invasive techniques for diagnosis and treatment drive these costs for non-muscle invasive bladder cancer. Fluorescence cystoscopy increases the detection of superficial bladder cancer and reduces costs by improving the quality of resection and reducing recurrences. Radical cystectomy with intestinal diversion is the mainstay of treatment of invasive disease; however it is associated with substantial cost and morbidity. Increased efforts to improve the surgical management of bladder cancer while reducing the cost of treatment are increasingly necessary.

Key points

  • Bladder cancer is one of the most expensive cancers to treat; however, funding for research, discovery, and innovation is relatively lacking.

  • Blue-light cystoscopy is a novel diagnostic and therapeutic technique that improves detection of superficial bladder cancer and reduces costs associated with tumor recurrence.

  • Alvimopan, an oral opioid receptor antagonist, reduces the incidence and costs of complications associated with postoperative ileus after radical cystectomy and small bowel urinary diversion.

  • Robot-assisted radical cystectomy is an oncologically acceptable alternative to open cystectomy; however, further investigation is necessary to determine the cost-effectiveness of this technology.

Introduction

From diagnosis to death, bladder cancer is the most expensive malignancy to treat in the United States, with estimated expenditures of up to $187,000 per incident case. Bladder cancer treatment accounted for approximately $4 billion in direct costs to the US health care system in 2010 and is expected to exceed $5 billion by 2020.

Direct costs related to the management of non-muscle invasive bladder cancer (NMIBC) are driven by regular surveillance cystoscopies, frequent cross-sectional imaging and repetitive transurethral resections of bladder tumors (TURBT), and intravesical therapies. Patients typically have prolonged survival with frequent recurrences resulting in the high lifetime cost of this disease. Given that approximately 75% of incident cases are in this subgroup, the potential economic and public health impact of innovation in NMIBC is substantial.

For patients with muscle-invasive bladder cancer (MIBC), the standard of care is radical cystectomy (RC) with bilateral pelvic lymph node dissection and urinary diversion. Despite improvements in surgical techniques and postoperative recovery pathways, this complex and challenging procedure remains highly morbid with up to 60% of patients experiencing a complication and 25% requiring readmission to the hospital within 30 days. In addition to the high cost of surgery and management of subsequent complications, perioperative chemotherapy, and frequent cross-sectional surveillance imaging, as well as high end-of-life costs, contribute to the substantial financial burden of advanced disease. In addition to the direct medical costs associated with health services expenditures, the societal value of life lost because of untimely death from bladder cancer in the year 2000 alone is estimated to be as high as $17 billion.

Surgical advancements and novel diagnostic and therapeutic techniques are essential to improve bladder cancer outcomes and reduce the burden of suffering. However, the cost-effectiveness of these advances has never been more relevant as pressure mounts on the health care system to contain costs. Bladder cancer represents an enormous opportunity to maximize the value of treatment to improve outcomes while reducing excessive expenditures. This article examines the effectiveness and costs associated with recent advances in the surgical management of bladder cancer. In the first section, the evidence regarding blue light cystoscopy as an innovation in NMIBC is discussed; subsequently, with regard to patient care for higher risk disease, the novel perioperative pharmaceutical, alvimopam, and robotic-assisted radical cystectomy (RARC) are evaluated.

Introduction

From diagnosis to death, bladder cancer is the most expensive malignancy to treat in the United States, with estimated expenditures of up to $187,000 per incident case. Bladder cancer treatment accounted for approximately $4 billion in direct costs to the US health care system in 2010 and is expected to exceed $5 billion by 2020.

Direct costs related to the management of non-muscle invasive bladder cancer (NMIBC) are driven by regular surveillance cystoscopies, frequent cross-sectional imaging and repetitive transurethral resections of bladder tumors (TURBT), and intravesical therapies. Patients typically have prolonged survival with frequent recurrences resulting in the high lifetime cost of this disease. Given that approximately 75% of incident cases are in this subgroup, the potential economic and public health impact of innovation in NMIBC is substantial.

For patients with muscle-invasive bladder cancer (MIBC), the standard of care is radical cystectomy (RC) with bilateral pelvic lymph node dissection and urinary diversion. Despite improvements in surgical techniques and postoperative recovery pathways, this complex and challenging procedure remains highly morbid with up to 60% of patients experiencing a complication and 25% requiring readmission to the hospital within 30 days. In addition to the high cost of surgery and management of subsequent complications, perioperative chemotherapy, and frequent cross-sectional surveillance imaging, as well as high end-of-life costs, contribute to the substantial financial burden of advanced disease. In addition to the direct medical costs associated with health services expenditures, the societal value of life lost because of untimely death from bladder cancer in the year 2000 alone is estimated to be as high as $17 billion.

Surgical advancements and novel diagnostic and therapeutic techniques are essential to improve bladder cancer outcomes and reduce the burden of suffering. However, the cost-effectiveness of these advances has never been more relevant as pressure mounts on the health care system to contain costs. Bladder cancer represents an enormous opportunity to maximize the value of treatment to improve outcomes while reducing excessive expenditures. This article examines the effectiveness and costs associated with recent advances in the surgical management of bladder cancer. In the first section, the evidence regarding blue light cystoscopy as an innovation in NMIBC is discussed; subsequently, with regard to patient care for higher risk disease, the novel perioperative pharmaceutical, alvimopam, and robotic-assisted radical cystectomy (RARC) are evaluated.

Blue-light cystoscopy

Rationale

Complete TURBT is paramount to optimizing oncologic outcomes and minimizing costs. Approximately 60% of patients with newly diagnosed NMIBC have an “early recurrence” within 1 year after initial TURBT. Because nearly one-third of patients undergoing repeat TURBT within 6 weeks of initial resection have residual tumor, a substantial proportion of these recurrences may represent incomplete initial resection. Although solitary, pedunculated, papillary lesions are adequately visualized and resected with traditional white-light cystoscopy (WLC), the risk of incomplete detection and/or tumor resection with WLC is particularly high with flat, sessile, multifocal lesions characteristic of carcinoma in situ (CIS). Intravesical therapies are intended to treat and prevent implantation of microscopic tumor cells rather than gross residual tumor burden. Recurrence, progression, and overall prognosis are therefore strongly predicated on the completeness of the initial TURBT.

Description

Blue-light cystoscopy (BLC) or fluorescence cystoscopy was developed to improve detection to increase the likelihood of complete TURBT. This optical-imaging technology uses a photosensitizing agent in combination with blue-light illumination (380–450 nm) to help differentiate between malignant and benign urothelium. The photosensitizing agent is actively transported into urothelial cytoplasm and incorporated by the cellular heme-biosynthesis metabolism. The photoactive component (photoporphyrin IV) accumulates in cancerous and precancerous cells as a result of abnormal enzyme activity, while normal tissue eliminates the photoactive substance. When illuminated by blue light, abnormal cells fluoresce red from the accumulation of photoporphyrins and are more easily differentiated from the bluish-green appearance of normal cells.

The original photosensitizing agent, 5-amnolevulinic acid (5-ALA), required a 2- to 4-hour intravesical dwell time before TURBT and is no longer commercially available. Hexaminolevulinate (HAL; Cysview, PhotoCure Inc, Princeton, NJ, USA; formerly Hexvix, Photocure ASA, Oslo, Norway) is a derivative of 5-ALA that was approved for use in Europe in 2006 and in the United States in 2010. HAL and 5-ALA are equally effective ; however, HAL is more stable in white light, has better fluorescent intensity, has more homogeneous enhancement and distribution within photoactive porphyrins, and requires only 1 hour of dwell time.

Efficacy

Literature summary

Two meta-analyses by were published in 2013 by Yuan and colleagues (12 articles from 11 studies, 2258 patients, 1114 receiving BLC, including patients receiving 5-ALA and HAL) and Burger and colleagues (10 articles from 9 studies, 2212 patients, 1345 receiving BLC, only HAL). The meta-analysis by Burger and colleagues used raw patient-level data from prospective studies of patients receiving only HAL and provides the strongest level of evidence for the benefit of BLC. Rink and colleagues also published a systematic review of 44 studies comparing both 5-ALA and HAL with WLC in 2013.

Increased detection

Ta/T1

Burger and colleagues demonstrated significant improvement in the detection of papillary lesions with BLC using HAL (95% vs 86%, odds ratio [OR] 4.9 P<.0001). The odds of detecting a T1 lesion were 2.3 times higher with BLC than with WLC. One in 4 patients had at least 1 additional tumor detected by BLC that was missed with WLC in this meta-analysis. This proportion of patients with a missed tumor on WLC detected by BLC was significant in both primary (20.7%) and recurrent (27.7%) disease as well as intermediate-risk (35.7%) and high-risk (27.0%) disease. The detection rate in studies reviewed by Rink and colleagues using BLC was 92% to 100% compared with 50% to 100% using WLC.

Carcinoma in situ

The odds of detecting CIS was 12.4 times higher with BLC than WLC (95% vs 59%, P <.0001) with 26.7% of patients having CIS detected only by BLC. Detection rates for CIS ranged from 49% to 100% with BLC and 5% to 68% with WLC in studies reviewed by Rink and colleagues.

Recurrence

Both meta-analyses demonstrated decreased risk of recurrence with BLC. Yuan and colleagues reported that BLC reduced recurrence from 47.8% to 32.7% (OR 0.5, 95% confidence interval [CI] 0.4–0.6; P <.00001). Burger and colleagues reported the recurrence was reduced from 45.4% to 34.5% with BLC (OR 0.8, 95% CI 0.6–0.9; P = .006). BLC was slightly more effective in reducing recurrences of CIS or T1 tumors (OR 0.7, P = .05) compared with Ta disease (0.8, P= .04). In this meta-analysis, the number needed to treat with BLC to avoid 1 tumor recurrence was 6. The time to first recurrence was 1.7 months longer with BLC than WLC (95% CI 0.9–2.5 months; P <.0001).

Progression-free survival

No difference in progression-free survival (PFS) was noted at 1 year. In studies reviewed by Rink and colleagues, PFS ranged from 89% to 98% with BLC and 89% to 95% with WLC. Yuan and colleagues also reported no difference in PFS (OR 0.9, 95% CI 0.6–1.2, P = .39). Because of the natural history of NMIBC, measuring PFS at 1 year may be too short of a follow-up period to evaluate the impact of BLC on this intermediate outcome.

Safety

No safety concerns were discovered in an evaluation of more than 2300 patients who received HAL with BLC in 6 controlled trials. No serious adverse events (SAEs) or deaths were definitively attributed to administration of HAL, while 8 SAEs in 6 patients were of uncertain relationship to HAL. Adverse events (AEs) leading to treatment discontinuation occurred in 0.8% of all patients who received HAL compared with 0.2% who only underwent WLC. Only 2 AEs in one patient had uncertain relationship to HAL. There was no increased toxicity with dwell time exceeding 1 hour and no apparent drug-drug, drug-food, or drug-disease interactions. Finally, no significant increase in AEs or anaphylactic reactions was identified with repeated use of HAL within a controlled trial setting or on postmarketing evaluation of greater than 200,000 procedures from 2004 to 2013, where 23% received HAL more than once and 8% received HAL more than twice. Nevertheless, the US Food and Drug Administration (FDA) approval remains limited to one-time dose due to a single anaphylactic event after repeat administration that was not clearly related to HAL.

Guidelines and Recommendations

The European Association of Urology (EAU) recommends using BLC with HAL at initial TURBT. Although the International Consortium of Urologic Diseases (ICUD) suggests BLC improves tumor detection on initial TURBT, particularly with CIS, they make no definitive statement recommending routine use. The last iteration of the American Urological Association guidelines on NMIBC was completed before FDA approval of HAL and therefore offers no guidance. Several additional European and North American expert consensus groups echo the EAU recommendation for use on initial resection. Expert consensus statements from Europe and the United States recommend using BLC in several additional settings, as shown in Table 1 .

Table 1
Guidelines and expert consensus statements on the use of blue-light cystoscopy
Setting Bladder Cancer Guidelines (BCG) Expert Consensus Statements
EAU 2013 (Babjuk) ICUD-EAU 2013 (Burger) USA 2014 (Daneshmand) European 2014 (Witjes)
Initial TURBT + n/a + +
Positive cytology and negative WLC n/a + + +
Aid in diagnosis of CIS + + + +
Assess for suspected tumor recurrence n/a n/a + (+)
Follow-up of patients at intermediate to high risk of recurrence (high-grade T1, CIS, multifocal tumors) n/a n/a + +
In patients having received intravesical therapy (BCG) n/a n/a + a (+) b
In patients having repeat TURBT within 6 wk n/a n/a + (+)
Surveillance office cystoscopy or cystoscopy for hematuria workup n/a
As a training tool n/a +
Repeat TURBT in patients with high risk of recurrence who had prior TURBT with BLC n/a n/a n/a (+)
+, recommended; (+), recommended with proviso; −, insufficient data to recommend or not recommend; n/a, not reported.
Data from Refs.

a At least 3 mo after BCG.

b At least 6 wk after BCG.

Cost Analysis

Several European studies and one from the United States report cost comparison analyses with BLC and WLC. Additional expenditures with BLC included costs of the photodynamic medication, Foley catheters for instillation, increased surveillance cystoscopies for patients upstaged to high risk by BLC, and capital investment in BLC-compatible endoscopic equipment. Cost savings were primarily derived from fewer TURBTs. The studies varied slightly in their cost assumptions and duration of follow-up included in the analysis, as shown in Table 2 .

Table 2
Cost analyses of blue-light cystoscopy
Study Cost Savings in $/Person (Time Frame) Assumptions/Oncologic Outcomes Notes
Dindyal et al, 2008 712 (first year) 20% reduction in recurrence at 3 mo 20% fewer TURBTs 20% fewer doses of MMC 30% reduction in surveillance cystoscopies per year New cases of NMIBC in the UK Standardized HRG costs for TURBT, MMC, cystoscopy Uses 5-ALA for analysis
Sievert et al, 2009 173 (first 3–6 mo) 20% reduction in recurrence at 3 mo 20% fewer TURBTs New cases of NMIBC in Germany at single institution Includes costs of preoperative catheter and HAL, additional equipment costs for BLC amortised over 10 y, equipment and staffing costs for TURBT, pathology costs
Burger et al, 2007 208 (per year for 7 y) None, compared actual treatment and follow-up treatment costs in randomized cohort 60% fewer TURBTs per person (0.8 vs 2.0 per person in BLC vs WLC group) Patients randomized to WLC or BLC in single German center All patients with NMIBC underwent repeat TURBT at prior resection site after 6 wk, appropriate adjuvant intravesical therapy, and quarterly surveillance cystoscopy Mean follow-up of 7.1 y Included single additional expenditure for each patient receiving BLC to account for medication (5-ALA) and catheter Identical rates of progression to MIBC so these costs not analyzed
Otto et al, 2009 Low risk: 209 (per year for 8.3 y) Intermediate risk: 335 (per year for 8.3 y) High risk: 259 (per year for 8.3 y) Lower recurrence rate in BLC group (28 vs 57%) Long-term (8.3 y) follow-up of Burger et al, 2007 Separated cost analysis into risk subgroups
Malstrom et al, 2009 83 (first year) 40% reduction in recurrences 7% reduction in need for TURBT 1% reduction in surveillance cystoscopy 44% reduction in cystectomy Population-based modeling estimate of first-year cost saving to the Swedish health care system based on 2032 new bladder cancer cases Included costs of cystoscopy, TURBT, post-TURBT treatments (MMC and/or BCG for NMIBC, cystectomy, and/or chemotherapy for MIBC or metastatic disease)
Garfield et al, 2013 932 (first year) Model derived from incidence, recurrence, and progression rates as well as rates of treatment of MIBC from long-term follow-up of original clinical trial by Stenzl et al (Grossman, 2012) Tumor-free rate (31.8 vs 38% in WLC vs BLC groups) Median time to recurrence (9.6 vs 16.4 mo in WLC vs BLC groups) Overall development of MIBC (6.1 vs 3.1% in WLC vs BLC groups) Cystectomy for progression (7.9 vs 4.8% in WLC vs BLC groups) Probabilistic decision-tree model for overall US health care system costs using HAL BLC at initial diagnosis as adjunct to WLC over 5 y Did not take costs of capital equipment into account because modeling was from the perspective of reimbursement by payers Used median Medicare payment
Abbreviation: HRG, Healthcare Resource Group.
Data from Refs.

Utility/Quality of Life

To the extent that BLC reduces recurrences and the need for associated TURBTs, this technology is likely to improve patient quality of life (QOL), as suggested by Malmstrom and colleagues and Grossman and colleagues. To date, however, empirical data on the effect of BLC on QOL are limited.

Using statistical modeling based on clinical trials data, Marteau and colleagues estimated that patients receiving BLC spend 11% less time managing recurrences over a period of 5 years. In the absence of empirically derived utility scores for the relevant clinical states in the model, the actual effect on QOL remains somewhat speculative, but the concept of a QOL benefit associated with a reduction in recurrences and procedures required to manage these has face validity. Further research to elucidate the clinically relevant benefit of BLC on QOL is necessary.

Gaps in Knowledge and Further Research

Variation in the utilization of perioperative single-dose intravesical chemotherapy is a major confounder across the studies evaluating BLC. Only 45% of patients in the phase III North American trial received single-dose chemotherapy, and it was not administered systematically. O’Brien and colleagues found no recurrence reduction with BLC over a period of 1 year in 168 patients. However, despite attempting to administer single-dose mitomycin C (MMC) systematically, only 63% of patients undergoing BLC and 77% of patients undergoing WLC actually received the chemotherapy. Geavlete and colleagues, conversely, found a significant reduction in recurrence with BLC over a period of 2 years when all 239 patients in their study received single-dose MMC.

To address this limitation of the existing literature, the PHOTOdynamic trial recently opened in the United Kingdom ( www.controlled-trials.com/ISRCTN84013636 ). This trial plans to randomize 533 patients with newly diagnosed bladder cancer to BLC or WLC on initial TURBT, with systematic administration of perioperative intravesical chemotherapy, standardized risk-adjusted surveillance protocol, and appropriate adjuvant therapies.

Robot-assisted laparoscopic radical cystectomy

Introduction

In the context of treatment of patients with more advanced disease, minimally invasive approaches to RC with pelvic lymph node dissection were developed in hopes of reducing the substantial morbidity of one of the most technical and challenging operations performed by urologists. Menon and colleagues described the first report of the RARC in 2003. Utilization of this technology for extirpative bladder surgery has subsequently risen to more than 12% as of 2011. Given trends in the adoption of robotic prostatectomy, it is possible that a continued increase in the utilization of RARC may be seen because trainees are more frequently getting experience with RARC in residency, and an increasing number of practicing urologists become more comfortable with robotics through experience with prostate and kidney surgery. As with many surgical innovations, adoption of RARC has preceded rigorous outcome and cost-effectiveness analyses.

Safety and Oncologic Efficacy

Three systematic reviews with meta-analyses compare complications and surrogate markers of oncologic efficacy (soft tissue margin positivity rate and lymph node yield) between open radical cystectomy (ORC) and RARC. With only one prospective randomized trial included available for review, these analyses suffer from inclusion of primarily small, single-center retrospective studies with inherent selection biases.

In general, these reviews conclude that RARC is associated with lower complications, less blood loss, fewer blood transfusions, shorter length of stay (LOS), but longer operative times. Three additional small, nonrandomized studies and a propensity-matched population-based cohort study subsequently confirmed these findings.

Patients undergoing RARC have a favorable positive surgical margin rate and lymph node yield compared with ORC. A subsequent propensity matched cohort study supported these findings by demonstrating a higher overall lymph node yield and lower positive soft tissue margin rate.

Recognizing the inherent limitations of available data, RARC appears feasible and safe with satisfactory oncologic outcomes. In 2013, however, the EAU stated that they were unable to form definite conclusions regarding the long-term safety and efficacy of RARC because of the lack of high-level evidence and long-term follow-up.

Two subsequent prospective randomized trials comparing safety and oncologic outcomes between ORC and RARC were recently published, adding to the findings of the randomized controlled trial by Nix and colleagues in 2010 ( Table 3 ). The RAZOR multicenter randomized trial has completed accrual of 350 patients, with follow-up ongoing, and will provide more definitive high-level evidence in the near future.

Table 3
Randomized controlled trials comparing perioperative outcomes and oncologic efficiency between RARC and ORC
Authors Study Characteristics Complications (RARC vs ORC) Perioperative Factors (RARC vs ORC) Oncologic Efficacy (RARC vs ORC)
Nix et al, 2010 Prospective single-center noninferiority RCT N = 41 (RARC = 21, ORC = 20) Any complication: 33 vs 50% Total Clavien units: 1.7 vs 2.8 ( P = .05) OR time: 4.2 vs 3.5 h ( P <.0001) EBL: 274 vs 564 mL ( P = .0003) Time to BM: 3.2 vs 4.3 d ( P = .0003) In-house analgesia; 93.6 vs 151.6 mg ( P = .01) LOS 5.4 vs 6 d ( P = .42) LN yield: equivalent (18 vs 19, P = .5)
Parekh et al, 2013 Pilot prospective single center RCT N = 39 (RARC = 20, ORC = 19) Clavien 2 or greater: 25 vs 25% ( P = .5) OR time: 5.0 vs 4.75 h ( P = .33) EBL: 400 vs 800 mL (0.003) Transfusions (40 vs 50%, P = .27) LOS: 6 vs 6 d ( P = .29) LOS 5 d or less (35% vs 10%, P = .03) Days to diet: 4 vs 5.5 d ( P = .5) LN yield: equivalent 11 vs 23 ( P = .135) PSM: 5 vs 5% ( P = .5)
Bochner et al, 2014 Prospective single-center RCT N = 118 (RARC = 58, ORC = 60 Clavien 2–5: 62 vs 66% ( P = .66) Clavien 3–5: 22 vs 21% ( P = .9) OR time: 7.6 vs 5.5 h ( P <.001) EBL: 159 mL less with RARC LOS: 8 vs 8 d ( P = .53) n/a
Abbreviations: BM, bowel movement; EBL, estimated blood loss; LN, lymph node; OR, operating room; PSM, positive surgical margins; RARC, robot-assisted radical cystectomy; RCT, randomized control trial.
Data from Refs.

There is a relative paucity of high-quality long-term oncologic outcome data due to the relatively recent adoption of RARC. Two recent single-institution, retrospective analyses of the earliest RARC cohorts with 5- to 8-year follow-up suggest long-term oncologic outcomes comparable to ORC series, including overall, disease-specific, and disease-free survival. Prospective randomized controlled trials with long-term follow-up are necessary before making definitive conclusions about the safety and efficacy of RARC; however, preliminary data suggest similar outcomes.

Costs

Current cost assessments of RARC and ORC are limited to cost-identification analyses, which assume equivalent outcomes with both techniques. Long-term functional and oncologic outcomes are still maturing and have yet to be integrated into proper cost-effectiveness analyses using quality-adjusted life years (QALY). Additional challenges to effective cost assessments are the variable structure of robotic equipment purchases and maintenance, different operating room and hospitalization costs between institutions, and heterogeneous robotic operative experience.

Generally speaking, existing cost analyses of RARC account for additional direct fixed costs (initial robot purchase, maintenance, disposable instruments) and direct variable costs (operating room time) with indirect cost savings associated with reduced blood loss, fewer transfusions, avoidance of complications, shorter LOS, and decreased medication requirement. Additional theoretic cost benefits that have yet to be quantified in this particular context include faster convalescence with a reduction in lost productivity. Three single-institutional cost analyses have been performed with somewhat mixed results. These studies consider the direct and indirect costs mentioned above ( Table 4 ). The lack of long-term follow-up and clinical outcomes thus far limits the assessment of long-term costs.

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