Asymptomatic Recurrence Detection and Cost-Effectiveness in Urothelial Carcinoma - Beyond the Abstract
Whether regular surveillance after RC for MIBC or RNU for UTUC could improve oncological outcomes remains controversial due to surveillance-related biases and the lack of prospective studies. Additionally, most studies fail to demonstrate any survival benefit of regular surveillance in colorectal cancer 1, breast cancer 2, endometrial cancer 3, or lung cancer 4. Similarly, debates continue on whether regular oncological surveillance to detect asymptomatic recurrence after RC or RNU improves patient survival 5, 6. Furthermore, cost-effectiveness represents another important factor to consider for regular surveillance.
Although a larger number of screens increase the medical cost, less screening could translate into missing a chance for therapy. Several guidelines recommend regular oncological surveillance 7-10 , however, these guidelines do not address medical cost. Currently, no established cost-effective surveillance protocol after RC or RNU is available 7, 11, 12, and only a few studies have investigated a cost-effective surveillance protocol after RC 13 and RNU 14. We summarized the current evidence of the benefit and cost-effectiveness of regular oncological surveillance to detect recurrence after RC and RNU.
To date, seven retrospective studies have investigated the impact of detecting asymptomatic recurrence at regular surveillance after RC 5, 15-20 Of the seven studies, only one by Volkmer et al.15 reported no survival benefit of detecting asymptomatic recurrence and concluded that symptom-guided follow-up may provide similar results at lower cost. However, the authors excluded secondary urothelial recurrence from all postoperative recurrences, potentially underestimating the frequency of asymptomatic recurrences and lowering the oncological benefit of regular surveillance. Furthermore, they concluded the lack of benefit of detecting asymptomatic recurrence based on only a log-rank test without multivariate analysis. Conversely, the recent six studies using multivariate Cox regression analysis demonstrated the benefit of detecting asymptomatic recurrence 5, 16-20. Kusaka et al.5 evaluated the impact of symptomatic recurrence after RC in 581 patients. Their results showed that 53% of patients presented with symptoms at recurrence after RC and found that patients with symptomatic recurrence had a significantly worse prognosis than with asymptomatic recurrence. Patients with an asymptomatic recurrence frequently experienced lymph node recurrence, whereas symptomatic patients exhibited a larger number of local pelvic recurrence cases. In addition, they used an inverse probability of treatment weighting (IPTW) strategy to remove the effects of confounding factors. The IPTW-adjusted Cox regression analysis performs reweighting of affected and unaffected groups to emulate a propensity score-matched population 21 in order to evaluate the impact of symptomatic recurrence on prognosis. The IPTW-adjusted analysis showed that symptomatic recurrence was an independent risk factor for OS after RC (HR, 1.94; P < 0.001) and OS after recurrence (HR, 2.18; P < 0.001). From these retrospective studies, asymptomatic recurrence detection is suggested as an independent prognostic factor after RC (Fig. 1). Taken together these results suggest a clinical benefit of regular surveillance after RC; however, prospective studies are needed to confirm its potential benefit.
To date, only one study has investigated the clinical benefit of regular surveillance after RNU 6 (Table 1, Fig. 1). Horiguchi et al. 6 retrospectively reviewed 415 patients treated with RNU for UTUC at four hospitals in Japan. Their cohort included 108 (26%) patients with tumor recurrence. The number of patients with asymptomatic and symptomatic recurrences was 62/108 (57%) and 46/108 (43%) patients. Their results showed that patients with symptomatic recurrence had a significantly worse overall survival than those with asymptomatic recurrence 6. These findings are consistent with those of our previous study on symptomatic recurrence after RC5. Recurrence-free survival, CSS after RNU, and OS after recurrence were significantly longer in patients in the asymptomatic group than in those in the symptomatic group. IPTW-adjusted multivariate Cox regression analysis showed that symptomatic recurrence was an independent risk factor for OS after RNU (HR, 1.75; P = 0.040) and OS after recurrence (HR, 2.08; P = 0.009) (Fig. 1). Therefore, regular oncological surveillance for detecting asymptomatic recurrence after RNU potentially improves prognosis. Although a prospective randomized study is required, the accumulation of retrospective studies is also needed because UTUC is a relatively rare disease 7, 22.
On regarding the oncological benefit of regular surveillance for asymptomatic recurrence detection, lead-time bias must be considered. Lead-time bias means that the survival duration after asymptomatic recurrence may be overestimated because surveillance-detected recurrence is generally detected earlier than symptomatic recurrence. Although there are no prospective studies to resolve lead-time bias in regular follow-up after RC or RNU, Osterman et al. 20 retrospectively attempted to account for lead-time bias in patients who underwent RC. They showed that symptomatic recurrence was diagnosed 1.7 months before asymptomatic recurrence; nevertheless, median survival after symptomatic recurrence was 8.2 months shorter than after asymptomatic recurrence. These results suggest that detecting asymptomatic recurrence after RC represents an oncological benefit, which cannot be explained by lead-time bias.
Risk factors for symptomatic recurrence remain unclear. Our result suggested that the use of neoadjuvant chemotherapy (NAC) and pathological risk associated (pT3–4, LVI, or pN+) were identified as independent factors for symptomatic recurrence in both MIBC and UTUC. One possible reason is the selection of the malignant clone during NAC for urothelial carcinoma. A recent study suggested a potential association between the MIB1 index (immunostaining for Ki67), a proliferation marker, and NAC use 23. Hosogoe et al. reported the MIB1 index was significantly higher in patients with UTUC with NAC compared to those without NAC 23. The median MIB1 index was significantly higher in the patients with NAC (21%; IQR, 6.9%–44%) than in those without NAC (3.3%; IQR, 1.9%–12%). In addition, the median MIB1 index was significantly higher in patients with relapse than in those without relapse in the patients with NAC (16% vs 39%) but did not differ in those without NAC (4.0% vs 2.4%). The authors suggested that MIB1 index > 20% was significantly associated with poor progression-free survival in patients with UTUC with NAC. Therefore, selection of the malignant clone during NAC may impact tumor aggressiveness and resulted in symptomatic recurrence whereas the total number of recurrence events decreased after NAC 23. Although further studies are necessary to elucidate the relationship between symptomatic recurrence and NAC use, close attention is recommended when patients with urothelial carcinoma have LVI and higher MIB1 index after RC or RNU.
Expensive follow-up cost is justified only when surveillance leads to improved patient survival. Asymptomatic recurrence identification implies effectiveness of regular surveillance; however, there are no clear guidelines on how to appropriately follow-up patients after RC 12 or RNU 7, 11, 24. With more screening, asymptomatic recurrence can be detected earlier; however, the cost will increase accordingly. A few studies have investigated the cost-effectiveness of surveillance protocols 13, 14, 25. Kusaka et al. 13 and Momota et al. 14 developed a risk-score-stratified surveillance protocol with improved cost-effectiveness after RC and RNU., respectively. The risk-score-based protocol led to a dramatic 5-year screening cost reduction compared to the pathology-based protocol after RC (48% reduction) and UTUC (55% reduction) for estimated 5-year screening cost.
Although asymptomatic recurrence detected by regular surveillance potentially results in better oncological outcomes after RC or RNU, the prognostic benefit of regular oncological surveillance remains unclear. The establishment of optimal risk stratification and surveillance strategies are required to improve the efficacy of regular oncological surveillance. Well-planned prospective studies are necessary to address the prognostic benefit of regular oncological surveillance and shared decision making.
Written by: Shingo Hatakeyama, MD, Department of Urology, Hirosaki University Graduate School of Medicine, Hirosak, Japan
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