Asymptomatic recurrence detection and cost-effectiveness in urothelial carcinoma

Asymptomatic recurrence detection and cost-effectiveness in urothelial carcinoma For the management of muscle-invasive bladder cancer or upper tract urothelial carcinoma, the set guidelines recommend regular surveillance after radical cystectomy or radical nephroureterectomy. However, the prognostic benefit of regular oncological surveillance remains controversial in the absence of prospective studies although several retrospective studies with relatively large sample sizes have demonstrated the association between asymptomatic recurrence and better oncologi- cal outcomes. Seven out of eight studies reported that patients diagnosed with symptomatic recurrence showed significantly poorer prognosis in comparison to those diagnosed with asymptomatic recurrence. However, potential lead-time and length- time biases prevent the determination of any benefit of regular surveillance. In addition, an optimal surveillance protocol has yet to be established because conventional pathology-based protocols cannot identify the heterogenetic tumor biology of urothelial carcinoma, such as rapid- or slow-growing form of the disease. Several studies suggest that conventional pathology-based surveillance resulted in reduced cost-effectiveness. Recurrence risk-score stratified surveillance protocol including clinical and pathological factors may improve cost-effectiveness. The establishment of optimal risk stratification and surveillance strategies are required to improve the efficacy of regular oncological surveillance. Well-planned prospec- tive studies are necessary to address the prognostic benefit of regular oncological surveillance and shared decision making. Keywords Cystectomy · Nephroureterectomy · Urothelial carcinoma · Recurrence · Surveillance · Symptomatic · Cost- effectiveness Introduction detection followed by salvage therapies is generally consid- ered important [5, 9–12]. Whether regular surveillance after Radical cystectomy (RC) and radical nephroureterectomy RC for MIBC or RNU for UTUC could improve oncological (RNU) are standard therapy for muscle-invasive bladder can- outcomes remains controversial due to surveillance-related cer (MIBC) and upper tract urothelial carcinoma (UTUC), biases and the lack of prospective studies. Additionally, most respectively [1–8]. Because recurrence after radical sur- studies fail to demonstrate any survival benefit of regular gery for urothelial carcinoma leads to poor prognosis, early surveillance in colorectal cancer [13], breast cancer [14], endometrial cancer [15], or lung cancer [16]. Similarly, debates continue on whether regular oncological surveil- * Shingo Hatakeyama lance to detect asymptomatic recurrence after RC or RNU shingoh@hirosaki-u.ac.jp improves patient survival [17, 18]. Furthermore, cost-effec- Hiromichi Iwamura tiveness represents another important factor to consider for hiro_hiro388@yahoo.co.jp regular surveillance. Although larger number of screens Makoto Sato increase the medical cost, less screening could translate into ms.hifu@tohoku-mpu.ac.jp missing a chance for therapy. Several guidelines recommend Chikara Ohyama regular oncological surveillance [5, 10–12]; however, these coyama@hirosaki-u.ac.jp guidelines do not address medical cost. Currently, no estab- Department of Urology, Hirosaki University Graduate lished cost-effective surveillance protocol after RC or RNU School of Medicine, 5 Zaifu-cho, Hirosak 036-8562, Japan is available [5, 19, 20], and only few studies have investi- Department of Urology, Tohoku Medical and Pharmaceutical gated a cost-effective surveillance protocol after RC [21] and University, 1-15-1 Fukumuro, Sendai 983-8536, Japan Vol.:(0123456789) 1 3 94 Page 2 of 10 Medical Oncology (2018) 35:94 RNU [22]. This review summarizes the current evidences recurrence based on only a log-rank test without multivari- of the benefit and cost-effectiveness of regular oncological ate analysis. Conversely, the recent six studies using mul- surveillance to detect recurrence after RC and RNU. tivariate Cox regression analysis demonstrated the benefit of detecting asymptomatic recurrence [17, 26–30]. Gian- narini et al. [26] reviewed 479 patients who underwent RC Asymptomatic recurrence and oncological with orthotopic ileal neobladder reconstruction and showed outcomes that patients diagnosed with symptomatic recurrence during regular surveillance had significantly worse cancer-specific MIBC survival (CSS) and overall survival (OS) compared to those diagnosed with asymptomatic recurrence [CSS: hazard ratio Despite advances in surgical techniques and neoadjuvant/ (HR) 1.54; P = 0.013 and OS: HR 1.51; P = 0.015] (Fig. 1). adjuvant chemotherapies for MIBC, approximately 38–49% Boorjian et al. [27] retrospectively investigated 1599 patients of patients experience disease recurrence within 10 years who underwent RC and demonstrated that symptomatic after RC [2, 9, 23]. Once metastatic disease has occurred, recurrence was an independent risk factor for worse OS its prognosis is dismal due to limited and transient benefit (HR 1.59; P = 0.0001) (Fig. 1). Nieuwenhuijzen et al. [28] of salvage therapy, and the median survival after recurrence also reviewed 343 patients treated with RC and reported is approximately 12–14 months [24]. Therefore, the benefit that symptomatic recurrence was adversely associated of regular oncological follow-up to detect asymptomatic with CSS (HR 2.40; P = 0.013) (Fig. 1). Alimi et al. [29] recurrence has been questioned. To date, seven retrospective reported the prognostic disadvantage of symptomatic recur- studies have investigated the impact of detecting asympto- rence in a series of 331 patients who underwent RC (CSS: matic recurrence at regular surveillance after RC [17, 25–30] HR 1.81; P = 0.049) (Fig. 1). Similarly, Osterman et al. [30] (Table 1; Fig. 1). Of the seven studies, only one by Volkmer reviewed 463 patients who underwent RC and showed worse et al. [25] reported no survival benefit of detecting asymp- OS in the symptomatic group than in the asymptomatic tomatic recurrence and concluded that symptom-guided fol- group (HR 1.74; P < 0.05) (Fig. 1). Furthermore, Kusaka low-up may provide similar results at lower cost. However, et al. [17] evaluated the impact of symptomatic recurrence the authors excluded secondary urothelial recurrence from after RC in 581 patients. Their results showed that 53% of all postoperative recurrences, potentially underestimating patients presented with symptoms at recurrence after RC the frequency of asymptomatic recurrences and lowering and found that patients with symptomatic recurrence had a the oncological benefit of regular surveillance. Furthermore, significantly worse prognosis than with asymptomatic recur - they concluded the lack of benefit of detecting asymptomatic rence. Patients with an asymptomatic recurrence frequently Table 1 Summary of previous studies for prognostic risk of symptomatic recurrence after radical cystectomy or radical nephroureterectomy Authors (year) No. of patients No. of patients Symptomatic ver- Prognostic risk of sympto- Analysis with recurrence sus asymptomatic matic recurrence (%) (%) Bladder cancer  Volkmer et al. (2009) 1,270 444 (49%) 65% versus 35% No (not significant in OS) Univariate, log rank test  Giannarini et al. (2010) 479 174 (36%) 50% versus 50% Yes (HR 1.51, P = 0.015 Multivariate Cox regression in OS) analysis  Boorjian et al. (2011) 1,599 606 (38%) 77% versus 23% Yes (HR 1.59, P = 0.0001 Multivariate Cox regression in OS) analysis  Nieuwenhuijzen et al. 343 158 (46%) 64% versus 36% Yes (HR 2.40, P = 0.013 Multivariate Cox regression (2013) in CSS) analysis  Alimi et al. (2016) 331 160 (49%) 81% versus 19% Yes (HR 1.81, P = 0.040 Multivariate Cox regression in CSS) analysis  Kusaka et al. (2017) 581 175 (30%) 53% versus 47% Yes (HR 1.94, P < 0.001 IPTW-adjusted multivariate in OS) Cox regression analysis  Osterman et al. (2017) 463 197 (43%) 54% versus 36% Yes (HR 1.74, P < 0.05 Multivariate Cox regression in OS) analysis UTUC  Horiguchi et al. (2017) 415 108 (26%) 43% versus 57% Yes (HR 2.08, P = 0.009 IPTW-adjusted multivariate in OS) Cox regression analysis OS overall survival, CSS cancer-specific survival, HR hazard ratio, IPTW inverse probability of treatment weighting 1 3 Medical Oncology (2018) 35:94 Page 3 of 10 94 Fig. 1 Summary of previous HR for symptomatic recurrence studies aimed at investigat- 2.40 ing the impact of detecting 2.5 Asymp asymptomatic recurrence during Symp 2.08 regular surveillance after radical 1.94 2.0 1.81 cystectomy. Multivariate Cox 1.74 1.59 regression analysis shows that 1.51 1.5 patients diagnosed with sympto- matic recurrence during regular surveillance have significantly 1.0 worse prognosis compared to 11 111 1 those diagnosed with asympto- 0.5 matic recurrence 0.0 MIBC MIBC MIBC MIBC MIBC MIBC UTUC experienced lymph node recurrence, whereas symptomatic recurrences was 62/108 (57%) and 46/108 (43%) patients. patients exhibited larger number of local pelvic recurrence Their results showed that patients with symptomatic recur- cases. In addition, they used an inverse probability of treat- rence had a significantly worse overall survival than those ment weighting (IPTW) strategy to remove the effects of with asymptomatic recurrence [18]. These findings are confounding factors. The IPTW-adjusted Cox regression consistent with those of our previous study on sympto- analysis performs reweighting of affected and unaffected matic recurrence after RC [17]. Recurrence-free survival, groups to emulate a propensity score-matched population CSS after RNU, and OS after recurrence were significantly [31] in order to evaluate the impact of symptomatic recur- longer in patients in the asymptomatic group than in those rence on prognosis. The IPTW-adjusted analysis showed in the symptomatic group. IPTW-adjusted multivariate Cox that symptomatic recurrence was an independent risk factor regression analysis showed that symptomatic recurrence for OS after RC (HR 1.94; P < 0.001) and OS after recur- was an independent risk factor for OS after RNU (HR 1.75; rence (HR 2.18; P < 0.001). From these retrospective studies, P = 0.040) and OS after recurrence (HR 2.08; P = 0.009) asymptomatic recurrence detection is suggested as an inde- (Fig.  1). Therefore, regular oncological surveillance for pendent prognostic factor after RC (Fig. 1). Taken together, detecting asymptomatic recurrence after RNU potentially these results suggest a clinical benefit of regular surveillance improves prognosis. Although a prospective randomized after RC; however, prospective studies are needed to confirm study is required, accumulation of retrospective studies is its potential benefit. also needed because UTUC is a relatively rare disease [5, 32]. UTUC The standard treatment for non-metastatic UTUC is RNU Impact of lead‑time bias on outcomes with bladder cuff excision [5 , 7, 8, 11], and regular sur- veillance after RNU is considered necessary. Although the On regarding the oncological benefit of regular surveillance rationale for regular surveillance is a better prognosis based for asymptomatic recurrence detection, lead-time bias must on earlier recurrence detection, evidence proving the benet fi be considered. Lead-time bias means that the survival dura- of detecting asymptomatic recurrence after RNU is scarce. tion after asymptomatic recurrence may be overestimated To date, only one study has investigated the clinical ben- because surveillance-detected recurrence is generally efit of regular surveillance after RNU [18] (Table  1; Fig. 1). detected earlier than symptomatic recurrence. Although Horiguchi et al. [18] retrospectively reviewed 415 patients there are no prospective studies to resolve lead-time bias treated with RNU for UTUC at four hospitals in Japan. Their in regular follow-up after RC or RNU, Osterman et al. [30] cohort included 108 (26%) patients with tumor recurrence. retrospectively attempted to account for lead-time bias in The number of patients with asymptomatic and symptomatic patients who underwent RC. They showed that symptomatic 1 3 Giannarini et al Boorjian et al Nieuwenhuijzen et al. Alimi et al Kusaka et al Osterman et al Horiguchi et al HR 94 Page 4 of 10 Medical Oncology (2018) 35:94 recurrence was diagnosed 1.7 months before asymptomatic Table 2 Multivariate Cox regression analysis for symptomatic recur- rence after radical cystectomy (n = 610) or radical nephroureterec- recurrence; nevertheless, median survival after symptomatic tomy (n = 456) recurrence was 8.2 month shorter than after asymptomatic Risk factor P value HR 95% CI recurrence. These results suggest that detecting asympto- matic recurrence after RC represents an oncological benefit, MIBC which cannot be explained by lead-time bias.  Age Continuous 0.247 1.01 0.99–1.04  Sex Male 0.193 0.73 0.45–1.17  CVD Positive 0.880 1.04 0.62–1.76 Risk factors for symptomatic recurrence  DM Positive 0.595 1.19 0.63–2.26  Preoperative Continuous 0.765 1.00 0.99–1.01 Symptomatic recurrence represents a failure of regular eGFR surveillance when it occurs through the regular follow-up  NAC Underwent 0.025 1.64 1.06–2.53 examinations. Identifying the risk factors for symptomatic  Urinary diversion Ileal neobladder 0.483 0.86 0.56–1.31 recurrence could contribute to improving the surveillance  Pathological risk pT3–4, LVI, or 0.029 1.67 1.05–2.64 protocol, resulting in better oncological outcomes after RC pN+ UTUC or RNU. Recently, Anan et al. [6] retrospectively investigated the risk factors for symptomatic recurrence in 581patients  Age Continuous 0.838 1.00 0.96–1.03  Sex Male 0.645 0.87 0.48–1.58 after RC, including 100 symptomatic and 75 asymptomatic recurrences. Symptomatic recurrences were significantly  CVD Positive 0.138 1.76 0.83–3.70  DM Positive 0.734 1.18 0.45–3.08 frequent within 24 months after RC. Multivariate Cox regression analysis identified lymphovascular invasion (LVI)  Preoperative Continuous 0.857 1.00 0.97–1.02 eGFR as an independent risk factor for symptomatic recurrence.  NAC Underwent 0.031 2.08 1.07–4.04 In addition, several previous studies [33–39] suggested the  Pathological risk pT3–4, LVI, or 0.001 1.37 1.14–1.65 association between preoperative severe renal insufficiency pN+ and symptomatic recurrence in patients with urothelial car- cinoma. Because no study has investigated the relationship CVD cardiovascular disease, DM diabetes mellitus, eGFR estimated glomerular filtration rate, NAC neoadjuvant chemotherapy between renal insuc ffi iency and symptomatic recurrence, we analyzed the impact of preoperative eGFR status on mode of recurrence in the same cohort reported by Momota et al. patients with UTUC with NAC compared to those without (MIBC, n = 610; UTUC, n = 456) [39]. Our analysis sug- gests that preoperative eGFR was not significantly differ - NAC [43]. The median MIB1 index was significantly higher in the patients with NAC (21%; IQR 6.9–44%) than in those ent between patients with asymptomatic and symptomatic recurrence (Fig. 2a) although it was significantly lower in without NAC (3.3%; IQR 1.9–12%) (Fig. 4a). In addition, the median MIB1 index was significantly higher in patients patients with recurrence compared to patients without recur- rence (Fig.  2b). In addition, multivariate Cox regression with relapse than in those without relapse in the patients with NAC (16% vs. 39%) but did not differ in those without analysis showed that eGFR was not an independent factor for symptomatic recurrence in both MIBC and UTUC. These NAC (4.0% vs. 2.4%) (Fig. 4b). The authors suggested that MIB1 index > 20% was significantly associated with poor results implied that preoperative eGFR could not identify the high-risk patients with symptomatic recurrence after radi- progression-free survival in patients with UTUC with NAC (Fig. 4c). Therefore, selection of the malignant clone dur- cal cystectomy or nephroureterectomy. In contrast, the use of neoadjuvant chemotherapy (NAC) and pathological risk ing NAC may impact tumor aggressiveness and resulted in symptomatic recurrence, whereas the total number of recur- associated (pT3–4, LVI, or pN+) were identified as inde- pendent factors for symptomatic recurrence in both MIBC rence events decreased after NAC [43]. Although further studies are necessary to elucidate the relationship between and UTUC (Table  2; Fig.  3a, b). These results suggest a significant impact of NAC on symptomatic recurrence in symptomatic recurrence and NAC use, close attention is rec- ommended when patients with urothelial carcinoma have urothelial carcinoma, although previous studies suggested significant risk reduction of NAC use for tumor recurrence LVI and higher MIB1 index after RC or RNU. Although detection of asymptomatic recurrence is asso- in both MIBC [40–42] and UTUC [43–45]. One possible reason is selection of the malignant clone during NAC for ciated with improved patient survival [17, 18, 26–30], the underlying reason may be linked to identifying the difference urothelial carcinoma. Recent study suggested a potential association between the MIB1 index (immunostaining for between rapid- and slow-growing tumors (i.e., length-time bias). In fact, the clinical characteristics of symptomatic and Ki67), a proliferation marker, and NAC use [43]. Hosogoe et al. reported the MIB1 index was significantly higher in asymptomatic recurrence are different. As a previous study 1 3 Medical Oncology (2018) 35:94 Page 5 of 10 94 Fig. 2 Association between eGFR and mode of recurrence eGFR and tumor recurrence A B renal function and mode of recurrence. Preoperative eGFR P=0.351 P<0.001 P=0.294 P<0.001 is not significantly different 100 100 between patients with asympto- matic and symptomatic recur- rence (a). Preoperative eGFR is 50 50 significantly lower in patients with recurrence than in those without recurrence (b) 0 0 Mode of rec. Asymp Symp Asymp Symp Recurrence (-) (+) (-) (+) Bladder Ca UTUC Bladder Ca UTUC n=188 n=117 n=610n=456 Fig. 3 Potential risk factors Risk for symp. recurrence (UTUC) A Risk for symp. recurrence (MIBC) B for symptomatic recurrence. Multivariate Cox regression Pathological risk NAC analysis shows that neoadjuvant NAC CVD chemotherapy (NAC) and the DM Pathological risk presence of pathological risk CVD (pT3–4, LVI, or pN+) are inde- DM Age pendent factors for symptomatic Preoperative eGFR Preoperative eGFR recurrence in MIBC (a) and Age UTUC (b) Urinary diversion Sex Sex 0.4 0.6 1.0 1.6 2.5 0.4 0.6 1.0 1.6 2.5 4.0 HR HR A B C MIB1 index MIB1 index and recurrence Progression-free survival (UTUC patients with NAC) P= 0.0117 P<0.001 100 60 60 MIB1 <20% 50 50 MIB1 20% 40 40 P=0.011 30 30 P= 0.5727 20 20 0 0 without NAC NAC Re currence (-) (+) (-) (+) 0 20 40 60 Months UTUC without NACNAC Fig. 4 Association between MIB1 index and neoadjuvant chemo- than in those without relapse (16% vs. 39%) but did not differ in those therapy (NAC) in patients with UTUC. MIB1 index is significantly without NAC (4.0% vs. 2.4%) (b). MIB1 index > 20% was signifi- higher in patients with UTUC treated with NAC (21%; IQR 6.9–44%) cantly associated with poor progression-free survival in patients with than in those without NAC (3.3%; IQR 1.9–12%) (a). The median UTUC treated with NAC (C) MIB1 index is significantly higher in patients with NAC with relapse suggested, symptomatic recurrences are more frequent in potential of tumors are required for a better understanding local pelvis and/or bone. However, asymptomatic recurrence of tumor biology. In recent times, the wide-spreading tech- are more frequently lymph node recurrences [17]. Tumor nology of gene testing may allow to predict organs that are progression that is missed during routine follow-up suggests likely to metastasize. Genome-based molecular is one of the a biological heterogeneity between rapid- and slow-growing potential biomarkers for phenotype classification [ 46–49]. tumors that cannot be detected by a conventional patho- The basal type of MIBC is associated with worse disease- logical examination. In addition to clinical or pathological specific and OS due to its highly invasive and metastatic information, novel biomarkers predicting the malignant potential [46]. This phenotype is also associated with an 1 3 MIB1 Index (% ) eGFR (mL/min/1.73m ) MIB1 Index (%) Percent survival eGFR (mL/min/1.73m ) 94 Page 6 of 10 Medical Oncology (2018) 35:94 epithelial–mesenchymal transition and bladder cancer stem- reviewed 581 patients after RC with regular oncological cell biomarkers [50]. Furthermore, the earlier detection of follow-up. The risk-scores were calculated by summing 6 recurrence is pivotal for the possibility to use immune- risk factors (LVI+, pN+, ≥ pT3 or surgical margin [SM]+, checkpoint inhibitors [51, 52] that potentially provide long- preoperative chronic kidney disease [CKD]+, cardiovascu- term survival for selected patients. Novel biomarkers pre- lar disease+, and non-neobladder) that were independently dicting the malignant potential of tumors can applied for associated with recurrence-free survival by multivariate surveillance schedules in future. analysis. Patients were classified into 3 groups; low-risk (0–1), intermediate-risk (2–3), and high-risk (4–6) groups (Table 3) [21]. Based on this risk stratification, the authors Cost‑effectiveness in regular follow‑up developed a risk-score-based protocol for oncological fol- after surgery low-up and evaluated the per-capita cost of recurrence detec- tion. The estimated per-capita cost of recurrence detection Expensive follow-up cost is justified only when surveil- was compared between the risk-score-based protocol and lance leads to improved patient survival. Asymptomatic the conventional pathology-based protocol. The risk-score- recurrence identification implies effectiveness of regular based protocol led to a dramatic cost reduction compared surveillance; however, there are no clear guidelines on how to the pathology-based protocol. The total estimated 5-year to appropriately follow-up patients after RC [20] or RNU [5, screening cost was 1.9-fold higher with the pathology-based 19, 53]. Based on the principle that most recurrences after protocol ($1,148,687) than with the risk-score-based proto- RC or RNU tend to occur within 2 years [9, 21, 22], several col ($613,901). Estimated cost differences reached $534,786 follow-up protocols have been suggested by guidelines [5, per recurrence detected, a suggested 48% reduction in this 10–12, 53] based on the low level of evidence, and these cohort (Fig. 5a) [21]. protocols are mainly stratified by pathological stage with- With respect to UTUC, only one study has investigated out considering the heterogeneity in patients who underwent the cost-effectiveness of regular oncological surveillance. RC or RNU. With more screening, asymptomatic recur- Momota et al. [22] developed a risk-score-stratified sur- rence can be detected earlier; however, cost will increase veillance protocol with improved cost-effectiveness after accordingly. A few studies have investigated the cost-effec- RNU. They retrospectively reviewed 426 patients after tiveness of surveillance protocols [21, 22, 54]. Vemana RNU with regular oncological follow-up. Risk-scores et al. [54] calculated the surveillance cost for 24 months were calculated by summing 7 risk factors (SM+, LVI+, after RC using the Surveillance, Epidemiology, and End ≥ pT3, preoperative CKD+, cN+ or pN+, hydronephro- Results data base. The actual follow-up cost per patient for sis+, and tumor in ureter) that were independently associ- 24 months was $1108, and follow-up cost will increase up ated with recurrence-free survival by multivariate analy- to 10.6-fold if surveillance were performed based on cur- sis. Patients were classified into 3 groups; low-risk (0–2), rent established guidelines [9–12, 55]. Kusaka et al. [21] intermediate-risk (3–5), and high-risk (6–12) groups developed a risk-score-stratified surveillance protocol with (Table  4) [22]. Based on this risk stratification, they improved cost-effectiveness after RC. They retrospectively developed a risk-score-based protocol for oncological Table 3 Risk-score-based classification for MIBC Variable Status Risk-score Cardiovascular disease Positive 1 Preoperative CKD Positive 1 Urinary diversion Non-neobladder 1 Pathological T stage ≥ pT3 or SM+ 1 Pathological N stage pN positive 1 Lymphovascular invasion Positive 1 Risk-score-based classification Sum of risk- score Low-risk 0−1 Intermediate-risk 2−3 High-risk 4−6 CKD chronic kidney disease, SM surgical margin 1 3 Medical Oncology (2018) 35:94 Page 7 of 10 94 Total surveillance cost for 5 years A Total surveillance cost for 5 years B High-risk High-risk High-risk Very high-risk Inter.-risk Inter.-risk High-risk Normal-risk Low-risk 1500000 Normal-risk Low-risk $ 747,929 $ 696,030 (55% reduction) (48% reduction) Pathology-based Risk-score-based Pathology-based Risk-score-based MIBC UTUC Fig. 5 Comparison of total surveillance cost for 5  years between RC (a). The estimated medical cost differences reached $747,929 pathology-based and risk-score-based protocols. The estimated medi- (55% reduction) in UTUC after RNU (b) cal cost differences reached $696,030 (48% reduction) in MIBC after Table 4 Risk-score-based classification for UTUC Variable Status Risk-score Tumor in ureter Positive 1 Hydronephrosis Positive 1 Lymph node involvement (cN+ or pN+) Positive 2 Preoperative CKD Positive 2 Pathological T stage pT3–4 2 Lymphovascular invasion Positive 2 Surgical margin Positive 2 Risk-score-based classification Sum of risk-score Low-risk 0−2 Intermediate-risk 3−5 High-risk 6−12 CKD chronic kidney disease follow-up and evaluated the per-capita cost of recurrence Limitations detection. The estimated per-capita cost of recurrence detection was compared between the risk-score-based The present review has several limitations. Firstly, it is an protocol and the conventional pathology-based protocol. accumulation of retrospective studies with a small number Their results suggested that the total estimated 5-year sur- of patients with recurrence. It is difficult to control all veillance cost was 2.2-fold higher with the pathology- variables including selection bias, the influence of lead- based protocol ($1,365,245) than with the risk-score- time biases, and other unmeasurable confounding factors. based protocol ($617,315). Estimated cost differences Secondly, results cannot be extrapolated independently to reached $747,929 per recurrence detected, a suggested other countries because of the difference in health insur - 55% reduction in this cohort (Fig. 5b) [22]. These results ance system. Despite these limitations, this review sup- suggested a higher cost of the conventional pathology- ports the idea that a cost-effective surveillance protocol based protocol and the importance of using surveillance following curative surgery would detect recurrence at the protocols considering clinical factors associated with early stages of disease. In addition, the detection with recurrence after RC or RNU. 1 3 Per-capita cost of recurrence detection ($) Per-capita cost of recurrence detection ($) 94 Page 8 of 10 Medical Oncology (2018) 35:94 cystectomy followed by U-shaped ileal neobladder construction asymptomatic recurrence should secure sufficient time to for female bladder cancer patients: oncological and functional out- implement a multimodal therapy after relapse. Although comes. Urology. 2010;75(6):1499–503. https://doi.or g/10.1016/j. a prospective randomized study comparing a symptom- urolo gy.2009.08.083. based surveillance would be ideal to clarify the survival 4. 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Oncologic outcomes for open and laparoscopic Well-planned prospective studies are necessary to address radical nephroureterectomy in patients with upper tract urothelial carcinoma. Int J Clin Oncol. 2018. https://doi.or g/10.1007/s1014 the prognostic benefit of regular oncological surveillance 7-018-1248-9. and shared decision making. 9. Yafi FA, Aprikian AG, Fradet Y, Chin JL, Izawa J, Rendon R, et al. Surveillance guidelines based on recurrence patterns after Funding This work was supported by a Grant-in-Aid for Scien- radical cystectomy for bladder cancer: the Canadian Bladder Can- tific Research (Nos. 15H02563, 15K15579, 17K11118, 17K11119, cer Network experience. BJU Int. 2012;110(9):1317–23. https :// 17K16768, 17K16770, 17K16771, 18K16681, 18K16682, 18K16717, doi.org/10.1111/j.1464-410X.2012.11133 .x. 18K16718, 18K16719, and 18K09157) from the Japan Society for the 10. Kubota Y, Nakaigawa N. 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Asymptomatic recurrence detection and cost-effectiveness in urothelial carcinoma

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Medicine & Public Health; Oncology; Hematology; Pathology; Internal Medicine
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Abstract

For the management of muscle-invasive bladder cancer or upper tract urothelial carcinoma, the set guidelines recommend regular surveillance after radical cystectomy or radical nephroureterectomy. However, the prognostic benefit of regular oncological surveillance remains controversial in the absence of prospective studies although several retrospective studies with relatively large sample sizes have demonstrated the association between asymptomatic recurrence and better oncologi- cal outcomes. Seven out of eight studies reported that patients diagnosed with symptomatic recurrence showed significantly poorer prognosis in comparison to those diagnosed with asymptomatic recurrence. However, potential lead-time and length- time biases prevent the determination of any benefit of regular surveillance. In addition, an optimal surveillance protocol has yet to be established because conventional pathology-based protocols cannot identify the heterogenetic tumor biology of urothelial carcinoma, such as rapid- or slow-growing form of the disease. Several studies suggest that conventional pathology-based surveillance resulted in reduced cost-effectiveness. Recurrence risk-score stratified surveillance protocol including clinical and pathological factors may improve cost-effectiveness. The establishment of optimal risk stratification and surveillance strategies are required to improve the efficacy of regular oncological surveillance. Well-planned prospec- tive studies are necessary to address the prognostic benefit of regular oncological surveillance and shared decision making. Keywords Cystectomy · Nephroureterectomy · Urothelial carcinoma · Recurrence · Surveillance · Symptomatic · Cost- effectiveness Introduction detection followed by salvage therapies is generally consid- ered important [5, 9–12]. Whether regular surveillance after Radical cystectomy (RC) and radical nephroureterectomy RC for MIBC or RNU for UTUC could improve oncological (RNU) are standard therapy for muscle-invasive bladder can- outcomes remains controversial due to surveillance-related cer (MIBC) and upper tract urothelial carcinoma (UTUC), biases and the lack of prospective studies. Additionally, most respectively [1–8]. Because recurrence after radical sur- studies fail to demonstrate any survival benefit of regular gery for urothelial carcinoma leads to poor prognosis, early surveillance in colorectal cancer [13], breast cancer [14], endometrial cancer [15], or lung cancer [16]. Similarly, debates continue on whether regular oncological surveil- * Shingo Hatakeyama lance to detect asymptomatic recurrence after RC or RNU shingoh@hirosaki-u.ac.jp improves patient survival [17, 18]. Furthermore, cost-effec- Hiromichi Iwamura tiveness represents another important factor to consider for hiro_hiro388@yahoo.co.jp regular surveillance. Although larger number of screens Makoto Sato increase the medical cost, less screening could translate into ms.hifu@tohoku-mpu.ac.jp missing a chance for therapy. Several guidelines recommend Chikara Ohyama regular oncological surveillance [5, 10–12]; however, these coyama@hirosaki-u.ac.jp guidelines do not address medical cost. Currently, no estab- Department of Urology, Hirosaki University Graduate lished cost-effective surveillance protocol after RC or RNU School of Medicine, 5 Zaifu-cho, Hirosak 036-8562, Japan is available [5, 19, 20], and only few studies have investi- Department of Urology, Tohoku Medical and Pharmaceutical gated a cost-effective surveillance protocol after RC [21] and University, 1-15-1 Fukumuro, Sendai 983-8536, Japan Vol.:(0123456789) 1 3 94 Page 2 of 10 Medical Oncology (2018) 35:94 RNU [22]. This review summarizes the current evidences recurrence based on only a log-rank test without multivari- of the benefit and cost-effectiveness of regular oncological ate analysis. Conversely, the recent six studies using mul- surveillance to detect recurrence after RC and RNU. tivariate Cox regression analysis demonstrated the benefit of detecting asymptomatic recurrence [17, 26–30]. Gian- narini et al. [26] reviewed 479 patients who underwent RC Asymptomatic recurrence and oncological with orthotopic ileal neobladder reconstruction and showed outcomes that patients diagnosed with symptomatic recurrence during regular surveillance had significantly worse cancer-specific MIBC survival (CSS) and overall survival (OS) compared to those diagnosed with asymptomatic recurrence [CSS: hazard ratio Despite advances in surgical techniques and neoadjuvant/ (HR) 1.54; P = 0.013 and OS: HR 1.51; P = 0.015] (Fig. 1). adjuvant chemotherapies for MIBC, approximately 38–49% Boorjian et al. [27] retrospectively investigated 1599 patients of patients experience disease recurrence within 10 years who underwent RC and demonstrated that symptomatic after RC [2, 9, 23]. Once metastatic disease has occurred, recurrence was an independent risk factor for worse OS its prognosis is dismal due to limited and transient benefit (HR 1.59; P = 0.0001) (Fig. 1). Nieuwenhuijzen et al. [28] of salvage therapy, and the median survival after recurrence also reviewed 343 patients treated with RC and reported is approximately 12–14 months [24]. Therefore, the benefit that symptomatic recurrence was adversely associated of regular oncological follow-up to detect asymptomatic with CSS (HR 2.40; P = 0.013) (Fig. 1). Alimi et al. [29] recurrence has been questioned. To date, seven retrospective reported the prognostic disadvantage of symptomatic recur- studies have investigated the impact of detecting asympto- rence in a series of 331 patients who underwent RC (CSS: matic recurrence at regular surveillance after RC [17, 25–30] HR 1.81; P = 0.049) (Fig. 1). Similarly, Osterman et al. [30] (Table 1; Fig. 1). Of the seven studies, only one by Volkmer reviewed 463 patients who underwent RC and showed worse et al. [25] reported no survival benefit of detecting asymp- OS in the symptomatic group than in the asymptomatic tomatic recurrence and concluded that symptom-guided fol- group (HR 1.74; P < 0.05) (Fig. 1). Furthermore, Kusaka low-up may provide similar results at lower cost. However, et al. [17] evaluated the impact of symptomatic recurrence the authors excluded secondary urothelial recurrence from after RC in 581 patients. Their results showed that 53% of all postoperative recurrences, potentially underestimating patients presented with symptoms at recurrence after RC the frequency of asymptomatic recurrences and lowering and found that patients with symptomatic recurrence had a the oncological benefit of regular surveillance. Furthermore, significantly worse prognosis than with asymptomatic recur - they concluded the lack of benefit of detecting asymptomatic rence. Patients with an asymptomatic recurrence frequently Table 1 Summary of previous studies for prognostic risk of symptomatic recurrence after radical cystectomy or radical nephroureterectomy Authors (year) No. of patients No. of patients Symptomatic ver- Prognostic risk of sympto- Analysis with recurrence sus asymptomatic matic recurrence (%) (%) Bladder cancer  Volkmer et al. (2009) 1,270 444 (49%) 65% versus 35% No (not significant in OS) Univariate, log rank test  Giannarini et al. (2010) 479 174 (36%) 50% versus 50% Yes (HR 1.51, P = 0.015 Multivariate Cox regression in OS) analysis  Boorjian et al. (2011) 1,599 606 (38%) 77% versus 23% Yes (HR 1.59, P = 0.0001 Multivariate Cox regression in OS) analysis  Nieuwenhuijzen et al. 343 158 (46%) 64% versus 36% Yes (HR 2.40, P = 0.013 Multivariate Cox regression (2013) in CSS) analysis  Alimi et al. (2016) 331 160 (49%) 81% versus 19% Yes (HR 1.81, P = 0.040 Multivariate Cox regression in CSS) analysis  Kusaka et al. (2017) 581 175 (30%) 53% versus 47% Yes (HR 1.94, P < 0.001 IPTW-adjusted multivariate in OS) Cox regression analysis  Osterman et al. (2017) 463 197 (43%) 54% versus 36% Yes (HR 1.74, P < 0.05 Multivariate Cox regression in OS) analysis UTUC  Horiguchi et al. (2017) 415 108 (26%) 43% versus 57% Yes (HR 2.08, P = 0.009 IPTW-adjusted multivariate in OS) Cox regression analysis OS overall survival, CSS cancer-specific survival, HR hazard ratio, IPTW inverse probability of treatment weighting 1 3 Medical Oncology (2018) 35:94 Page 3 of 10 94 Fig. 1 Summary of previous HR for symptomatic recurrence studies aimed at investigat- 2.40 ing the impact of detecting 2.5 Asymp asymptomatic recurrence during Symp 2.08 regular surveillance after radical 1.94 2.0 1.81 cystectomy. Multivariate Cox 1.74 1.59 regression analysis shows that 1.51 1.5 patients diagnosed with sympto- matic recurrence during regular surveillance have significantly 1.0 worse prognosis compared to 11 111 1 those diagnosed with asympto- 0.5 matic recurrence 0.0 MIBC MIBC MIBC MIBC MIBC MIBC UTUC experienced lymph node recurrence, whereas symptomatic recurrences was 62/108 (57%) and 46/108 (43%) patients. patients exhibited larger number of local pelvic recurrence Their results showed that patients with symptomatic recur- cases. In addition, they used an inverse probability of treat- rence had a significantly worse overall survival than those ment weighting (IPTW) strategy to remove the effects of with asymptomatic recurrence [18]. These findings are confounding factors. The IPTW-adjusted Cox regression consistent with those of our previous study on sympto- analysis performs reweighting of affected and unaffected matic recurrence after RC [17]. Recurrence-free survival, groups to emulate a propensity score-matched population CSS after RNU, and OS after recurrence were significantly [31] in order to evaluate the impact of symptomatic recur- longer in patients in the asymptomatic group than in those rence on prognosis. The IPTW-adjusted analysis showed in the symptomatic group. IPTW-adjusted multivariate Cox that symptomatic recurrence was an independent risk factor regression analysis showed that symptomatic recurrence for OS after RC (HR 1.94; P < 0.001) and OS after recur- was an independent risk factor for OS after RNU (HR 1.75; rence (HR 2.18; P < 0.001). From these retrospective studies, P = 0.040) and OS after recurrence (HR 2.08; P = 0.009) asymptomatic recurrence detection is suggested as an inde- (Fig.  1). Therefore, regular oncological surveillance for pendent prognostic factor after RC (Fig. 1). Taken together, detecting asymptomatic recurrence after RNU potentially these results suggest a clinical benefit of regular surveillance improves prognosis. Although a prospective randomized after RC; however, prospective studies are needed to confirm study is required, accumulation of retrospective studies is its potential benefit. also needed because UTUC is a relatively rare disease [5, 32]. UTUC The standard treatment for non-metastatic UTUC is RNU Impact of lead‑time bias on outcomes with bladder cuff excision [5 , 7, 8, 11], and regular sur- veillance after RNU is considered necessary. Although the On regarding the oncological benefit of regular surveillance rationale for regular surveillance is a better prognosis based for asymptomatic recurrence detection, lead-time bias must on earlier recurrence detection, evidence proving the benet fi be considered. Lead-time bias means that the survival dura- of detecting asymptomatic recurrence after RNU is scarce. tion after asymptomatic recurrence may be overestimated To date, only one study has investigated the clinical ben- because surveillance-detected recurrence is generally efit of regular surveillance after RNU [18] (Table  1; Fig. 1). detected earlier than symptomatic recurrence. Although Horiguchi et al. [18] retrospectively reviewed 415 patients there are no prospective studies to resolve lead-time bias treated with RNU for UTUC at four hospitals in Japan. Their in regular follow-up after RC or RNU, Osterman et al. [30] cohort included 108 (26%) patients with tumor recurrence. retrospectively attempted to account for lead-time bias in The number of patients with asymptomatic and symptomatic patients who underwent RC. They showed that symptomatic 1 3 Giannarini et al Boorjian et al Nieuwenhuijzen et al. Alimi et al Kusaka et al Osterman et al Horiguchi et al HR 94 Page 4 of 10 Medical Oncology (2018) 35:94 recurrence was diagnosed 1.7 months before asymptomatic Table 2 Multivariate Cox regression analysis for symptomatic recur- rence after radical cystectomy (n = 610) or radical nephroureterec- recurrence; nevertheless, median survival after symptomatic tomy (n = 456) recurrence was 8.2 month shorter than after asymptomatic Risk factor P value HR 95% CI recurrence. These results suggest that detecting asympto- matic recurrence after RC represents an oncological benefit, MIBC which cannot be explained by lead-time bias.  Age Continuous 0.247 1.01 0.99–1.04  Sex Male 0.193 0.73 0.45–1.17  CVD Positive 0.880 1.04 0.62–1.76 Risk factors for symptomatic recurrence  DM Positive 0.595 1.19 0.63–2.26  Preoperative Continuous 0.765 1.00 0.99–1.01 Symptomatic recurrence represents a failure of regular eGFR surveillance when it occurs through the regular follow-up  NAC Underwent 0.025 1.64 1.06–2.53 examinations. Identifying the risk factors for symptomatic  Urinary diversion Ileal neobladder 0.483 0.86 0.56–1.31 recurrence could contribute to improving the surveillance  Pathological risk pT3–4, LVI, or 0.029 1.67 1.05–2.64 protocol, resulting in better oncological outcomes after RC pN+ UTUC or RNU. Recently, Anan et al. [6] retrospectively investigated the risk factors for symptomatic recurrence in 581patients  Age Continuous 0.838 1.00 0.96–1.03  Sex Male 0.645 0.87 0.48–1.58 after RC, including 100 symptomatic and 75 asymptomatic recurrences. Symptomatic recurrences were significantly  CVD Positive 0.138 1.76 0.83–3.70  DM Positive 0.734 1.18 0.45–3.08 frequent within 24 months after RC. Multivariate Cox regression analysis identified lymphovascular invasion (LVI)  Preoperative Continuous 0.857 1.00 0.97–1.02 eGFR as an independent risk factor for symptomatic recurrence.  NAC Underwent 0.031 2.08 1.07–4.04 In addition, several previous studies [33–39] suggested the  Pathological risk pT3–4, LVI, or 0.001 1.37 1.14–1.65 association between preoperative severe renal insufficiency pN+ and symptomatic recurrence in patients with urothelial car- cinoma. Because no study has investigated the relationship CVD cardiovascular disease, DM diabetes mellitus, eGFR estimated glomerular filtration rate, NAC neoadjuvant chemotherapy between renal insuc ffi iency and symptomatic recurrence, we analyzed the impact of preoperative eGFR status on mode of recurrence in the same cohort reported by Momota et al. patients with UTUC with NAC compared to those without (MIBC, n = 610; UTUC, n = 456) [39]. Our analysis sug- gests that preoperative eGFR was not significantly differ - NAC [43]. The median MIB1 index was significantly higher in the patients with NAC (21%; IQR 6.9–44%) than in those ent between patients with asymptomatic and symptomatic recurrence (Fig. 2a) although it was significantly lower in without NAC (3.3%; IQR 1.9–12%) (Fig. 4a). In addition, the median MIB1 index was significantly higher in patients patients with recurrence compared to patients without recur- rence (Fig.  2b). In addition, multivariate Cox regression with relapse than in those without relapse in the patients with NAC (16% vs. 39%) but did not differ in those without analysis showed that eGFR was not an independent factor for symptomatic recurrence in both MIBC and UTUC. These NAC (4.0% vs. 2.4%) (Fig. 4b). The authors suggested that MIB1 index > 20% was significantly associated with poor results implied that preoperative eGFR could not identify the high-risk patients with symptomatic recurrence after radi- progression-free survival in patients with UTUC with NAC (Fig. 4c). Therefore, selection of the malignant clone dur- cal cystectomy or nephroureterectomy. In contrast, the use of neoadjuvant chemotherapy (NAC) and pathological risk ing NAC may impact tumor aggressiveness and resulted in symptomatic recurrence, whereas the total number of recur- associated (pT3–4, LVI, or pN+) were identified as inde- pendent factors for symptomatic recurrence in both MIBC rence events decreased after NAC [43]. Although further studies are necessary to elucidate the relationship between and UTUC (Table  2; Fig.  3a, b). These results suggest a significant impact of NAC on symptomatic recurrence in symptomatic recurrence and NAC use, close attention is rec- ommended when patients with urothelial carcinoma have urothelial carcinoma, although previous studies suggested significant risk reduction of NAC use for tumor recurrence LVI and higher MIB1 index after RC or RNU. Although detection of asymptomatic recurrence is asso- in both MIBC [40–42] and UTUC [43–45]. One possible reason is selection of the malignant clone during NAC for ciated with improved patient survival [17, 18, 26–30], the underlying reason may be linked to identifying the difference urothelial carcinoma. Recent study suggested a potential association between the MIB1 index (immunostaining for between rapid- and slow-growing tumors (i.e., length-time bias). In fact, the clinical characteristics of symptomatic and Ki67), a proliferation marker, and NAC use [43]. Hosogoe et al. reported the MIB1 index was significantly higher in asymptomatic recurrence are different. As a previous study 1 3 Medical Oncology (2018) 35:94 Page 5 of 10 94 Fig. 2 Association between eGFR and mode of recurrence eGFR and tumor recurrence A B renal function and mode of recurrence. Preoperative eGFR P=0.351 P<0.001 P=0.294 P<0.001 is not significantly different 100 100 between patients with asympto- matic and symptomatic recur- rence (a). Preoperative eGFR is 50 50 significantly lower in patients with recurrence than in those without recurrence (b) 0 0 Mode of rec. Asymp Symp Asymp Symp Recurrence (-) (+) (-) (+) Bladder Ca UTUC Bladder Ca UTUC n=188 n=117 n=610n=456 Fig. 3 Potential risk factors Risk for symp. recurrence (UTUC) A Risk for symp. recurrence (MIBC) B for symptomatic recurrence. Multivariate Cox regression Pathological risk NAC analysis shows that neoadjuvant NAC CVD chemotherapy (NAC) and the DM Pathological risk presence of pathological risk CVD (pT3–4, LVI, or pN+) are inde- DM Age pendent factors for symptomatic Preoperative eGFR Preoperative eGFR recurrence in MIBC (a) and Age UTUC (b) Urinary diversion Sex Sex 0.4 0.6 1.0 1.6 2.5 0.4 0.6 1.0 1.6 2.5 4.0 HR HR A B C MIB1 index MIB1 index and recurrence Progression-free survival (UTUC patients with NAC) P= 0.0117 P<0.001 100 60 60 MIB1 <20% 50 50 MIB1 20% 40 40 P=0.011 30 30 P= 0.5727 20 20 0 0 without NAC NAC Re currence (-) (+) (-) (+) 0 20 40 60 Months UTUC without NACNAC Fig. 4 Association between MIB1 index and neoadjuvant chemo- than in those without relapse (16% vs. 39%) but did not differ in those therapy (NAC) in patients with UTUC. MIB1 index is significantly without NAC (4.0% vs. 2.4%) (b). MIB1 index > 20% was signifi- higher in patients with UTUC treated with NAC (21%; IQR 6.9–44%) cantly associated with poor progression-free survival in patients with than in those without NAC (3.3%; IQR 1.9–12%) (a). The median UTUC treated with NAC (C) MIB1 index is significantly higher in patients with NAC with relapse suggested, symptomatic recurrences are more frequent in potential of tumors are required for a better understanding local pelvis and/or bone. However, asymptomatic recurrence of tumor biology. In recent times, the wide-spreading tech- are more frequently lymph node recurrences [17]. Tumor nology of gene testing may allow to predict organs that are progression that is missed during routine follow-up suggests likely to metastasize. Genome-based molecular is one of the a biological heterogeneity between rapid- and slow-growing potential biomarkers for phenotype classification [ 46–49]. tumors that cannot be detected by a conventional patho- The basal type of MIBC is associated with worse disease- logical examination. In addition to clinical or pathological specific and OS due to its highly invasive and metastatic information, novel biomarkers predicting the malignant potential [46]. This phenotype is also associated with an 1 3 MIB1 Index (% ) eGFR (mL/min/1.73m ) MIB1 Index (%) Percent survival eGFR (mL/min/1.73m ) 94 Page 6 of 10 Medical Oncology (2018) 35:94 epithelial–mesenchymal transition and bladder cancer stem- reviewed 581 patients after RC with regular oncological cell biomarkers [50]. Furthermore, the earlier detection of follow-up. The risk-scores were calculated by summing 6 recurrence is pivotal for the possibility to use immune- risk factors (LVI+, pN+, ≥ pT3 or surgical margin [SM]+, checkpoint inhibitors [51, 52] that potentially provide long- preoperative chronic kidney disease [CKD]+, cardiovascu- term survival for selected patients. Novel biomarkers pre- lar disease+, and non-neobladder) that were independently dicting the malignant potential of tumors can applied for associated with recurrence-free survival by multivariate surveillance schedules in future. analysis. Patients were classified into 3 groups; low-risk (0–1), intermediate-risk (2–3), and high-risk (4–6) groups (Table 3) [21]. Based on this risk stratification, the authors Cost‑effectiveness in regular follow‑up developed a risk-score-based protocol for oncological fol- after surgery low-up and evaluated the per-capita cost of recurrence detec- tion. The estimated per-capita cost of recurrence detection Expensive follow-up cost is justified only when surveil- was compared between the risk-score-based protocol and lance leads to improved patient survival. Asymptomatic the conventional pathology-based protocol. The risk-score- recurrence identification implies effectiveness of regular based protocol led to a dramatic cost reduction compared surveillance; however, there are no clear guidelines on how to the pathology-based protocol. The total estimated 5-year to appropriately follow-up patients after RC [20] or RNU [5, screening cost was 1.9-fold higher with the pathology-based 19, 53]. Based on the principle that most recurrences after protocol ($1,148,687) than with the risk-score-based proto- RC or RNU tend to occur within 2 years [9, 21, 22], several col ($613,901). Estimated cost differences reached $534,786 follow-up protocols have been suggested by guidelines [5, per recurrence detected, a suggested 48% reduction in this 10–12, 53] based on the low level of evidence, and these cohort (Fig. 5a) [21]. protocols are mainly stratified by pathological stage with- With respect to UTUC, only one study has investigated out considering the heterogeneity in patients who underwent the cost-effectiveness of regular oncological surveillance. RC or RNU. With more screening, asymptomatic recur- Momota et al. [22] developed a risk-score-stratified sur- rence can be detected earlier; however, cost will increase veillance protocol with improved cost-effectiveness after accordingly. A few studies have investigated the cost-effec- RNU. They retrospectively reviewed 426 patients after tiveness of surveillance protocols [21, 22, 54]. Vemana RNU with regular oncological follow-up. Risk-scores et al. [54] calculated the surveillance cost for 24 months were calculated by summing 7 risk factors (SM+, LVI+, after RC using the Surveillance, Epidemiology, and End ≥ pT3, preoperative CKD+, cN+ or pN+, hydronephro- Results data base. The actual follow-up cost per patient for sis+, and tumor in ureter) that were independently associ- 24 months was $1108, and follow-up cost will increase up ated with recurrence-free survival by multivariate analy- to 10.6-fold if surveillance were performed based on cur- sis. Patients were classified into 3 groups; low-risk (0–2), rent established guidelines [9–12, 55]. Kusaka et al. [21] intermediate-risk (3–5), and high-risk (6–12) groups developed a risk-score-stratified surveillance protocol with (Table  4) [22]. Based on this risk stratification, they improved cost-effectiveness after RC. They retrospectively developed a risk-score-based protocol for oncological Table 3 Risk-score-based classification for MIBC Variable Status Risk-score Cardiovascular disease Positive 1 Preoperative CKD Positive 1 Urinary diversion Non-neobladder 1 Pathological T stage ≥ pT3 or SM+ 1 Pathological N stage pN positive 1 Lymphovascular invasion Positive 1 Risk-score-based classification Sum of risk- score Low-risk 0−1 Intermediate-risk 2−3 High-risk 4−6 CKD chronic kidney disease, SM surgical margin 1 3 Medical Oncology (2018) 35:94 Page 7 of 10 94 Total surveillance cost for 5 years A Total surveillance cost for 5 years B High-risk High-risk High-risk Very high-risk Inter.-risk Inter.-risk High-risk Normal-risk Low-risk 1500000 Normal-risk Low-risk $ 747,929 $ 696,030 (55% reduction) (48% reduction) Pathology-based Risk-score-based Pathology-based Risk-score-based MIBC UTUC Fig. 5 Comparison of total surveillance cost for 5  years between RC (a). The estimated medical cost differences reached $747,929 pathology-based and risk-score-based protocols. The estimated medi- (55% reduction) in UTUC after RNU (b) cal cost differences reached $696,030 (48% reduction) in MIBC after Table 4 Risk-score-based classification for UTUC Variable Status Risk-score Tumor in ureter Positive 1 Hydronephrosis Positive 1 Lymph node involvement (cN+ or pN+) Positive 2 Preoperative CKD Positive 2 Pathological T stage pT3–4 2 Lymphovascular invasion Positive 2 Surgical margin Positive 2 Risk-score-based classification Sum of risk-score Low-risk 0−2 Intermediate-risk 3−5 High-risk 6−12 CKD chronic kidney disease follow-up and evaluated the per-capita cost of recurrence Limitations detection. The estimated per-capita cost of recurrence detection was compared between the risk-score-based The present review has several limitations. Firstly, it is an protocol and the conventional pathology-based protocol. accumulation of retrospective studies with a small number Their results suggested that the total estimated 5-year sur- of patients with recurrence. It is difficult to control all veillance cost was 2.2-fold higher with the pathology- variables including selection bias, the influence of lead- based protocol ($1,365,245) than with the risk-score- time biases, and other unmeasurable confounding factors. based protocol ($617,315). Estimated cost differences Secondly, results cannot be extrapolated independently to reached $747,929 per recurrence detected, a suggested other countries because of the difference in health insur - 55% reduction in this cohort (Fig. 5b) [22]. These results ance system. Despite these limitations, this review sup- suggested a higher cost of the conventional pathology- ports the idea that a cost-effective surveillance protocol based protocol and the importance of using surveillance following curative surgery would detect recurrence at the protocols considering clinical factors associated with early stages of disease. In addition, the detection with recurrence after RC or RNU. 1 3 Per-capita cost of recurrence detection ($) Per-capita cost of recurrence detection ($) 94 Page 8 of 10 Medical Oncology (2018) 35:94 cystectomy followed by U-shaped ileal neobladder construction asymptomatic recurrence should secure sufficient time to for female bladder cancer patients: oncological and functional out- implement a multimodal therapy after relapse. Although comes. Urology. 2010;75(6):1499–503. https://doi.or g/10.1016/j. a prospective randomized study comparing a symptom- urolo gy.2009.08.083. based surveillance would be ideal to clarify the survival 4. 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Journal

Medical OncologySpringer Journals

Published: May 9, 2018

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