T1 Substaging of Nonmuscle Invasive Bladder Cancer is Associated with bacillus Calmette-Guérin Failure and Improves Patient Stratification at Diagnosis

Open AccessJournal of UrologyAdult Urology1 Mar 2021T1 Substaging Nonmuscle Invasive Bladder Cancer is Associated with bacillus Calmette-Guérin Failure and Improves Patient Stratification at Diagnosis Florus C. de Jong, Robert F. Hoedemaeker, Vebjørn Kvikstad, Jolien T. M. Mensink, Joep J. Egbert R. Boevé, Deric K. E. van der Schoot, Ellen Zwarthoff, Joost L. Boormans, Tahlita Zuiverloon JongFlorus Jong Department Urology, Erasmus MC Institute, Rotterdam, The Netherlands More articles by this author , HoedemaekerRobert Hoedemaeker Pathan BV, Pathological Laboratory, KvikstadVebjørn Kvikstad Pathology, Stavanger University Hospital, Stavanger, Norway Mathematics Natural Science, MensinkJolien Mensink JongJoep BoevéEgbert Boevé Franciscus Gasthuis & Vlietland, SchootDeric Schoot Amphia, Breda, ZwarthoffEllen Zwarthoff BoormansJoost Boormans ZuiverloonTahlita *Correspondence: Medical Center, Dr. Molewaterplein 40, Room Be-304, 3015 GD, telephone: +31-107043059; FAX: +31-107044762; E-mail Address: [email protected] View All Author Informationhttps://doi.org/10.1097/JU.0000000000001422AboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Abstract Purpose: Currently, markers are lacking that can identify patients high risk nonmuscle invasive bladder cancer who will fail treatment. Therefore, we evaluated the prognostic value T1 substaging in primary cancer. Materials Methods: Patients received ?5 induction instillations were included. tumors centrally reviewed, which included (microinvasion vs extensive invasion lamina propria). stratified into or highest subgroups according major urology guidelines. Primary end point was failure, defined as development a grade recurrence. Secondary points recurrence-free survival, time from diagnosis biopsy-proven recurrence progression-free survival. Time-to-event analyses used predict Results: A total 264 had tumor propria, 73% classified 27% microinvasion. Median followup 68 months (IQR 43–98) failure more common among microinvasive (41% 21%, p=0.002). 3-year survival (defined Calmette-Guerin failure) for 64% 83% (p=0.004). In multivariate analysis, an independent predictor (HR 3.2, p=0.005) 3.0, p=0.009). risk/microinvasive disease have improved compared risk/T1e (p.adj=0.038). Conclusions: provides important information on treated Calmette-Guérin. higher tumors. has potential guide treatment decisions alternative strategies diagnosis. Abbreviations Acronyms BCG CIS carcinoma situ DSS disease-specific HG HG-RFS HPF (microscopic) high-powered field (objective 40×) HR-NMIBC LVI lymphovascular MIBC muscle MM-VP muscularis mucosae-vascular plexus p.adj adjusted p PFS RC radical cystectomy re-TURBT repeated transurethral resection T1e propria T1m microinvasion TaHG pTa TILs infiltrating lymphocytes VH variant histology accounts ?75% newly diagnosed cases.1 case (T1) invasion, recurrent progressive disease.2,3 adjuvant intravesical instillations.4 30%-50% HR-NMIBC, therapy fails these develop recurrences progression progression, neoadjuvant chemotherapy followed standard care.4 Despite treatment, 50%-70% progressed die within 5 years after diagnosis.5 No available benefit treatment.6 Repeated nonresponders cause delay recent study showed associated worse overall Furthermore, ongoing global shortage demands selective use limited resources. Thus, there clinical need should receive other treatments.7 To improve patient stratification, guidelines presence aggressive clinicopathological features subgroup progression.4,8 For patients, both American European strongly recommend consider immediate RC.4,8 substratification performing all results overtreatment.2,3 Over years, been investigated tool HR-NMIBC. Several methods described assess depth extent increased death.9–15 Some evidence deeper also disease.16,17 recommended pathologists since 2016 WHO classification.18 However, most optimal system remains be defined.19,20 evaluation (T1a/b MM-VP) challenging due difficult assessment metric (optical) micrometers impractical time-consuming.12,16 substaging, not exceed 1 HPF, easy proved accurate than earlier studies.9,21 it unknown if response unclear decisions. Here, whether method stratification Methods Pathology (Tis Ta/T1HG urothelial carcinoma), underwent without ?5/6 retrospectively 3 Dutch (Erasmus MC; Vlietland Amphia) Norwegian hospital (Stavanger Hospital) 2000–2017. Additional inclusion found supplementary (https://www.jurology.com). approved Ethics Committee (MEC-2018-1097). Hematoxylin eosin (HE) slides tumors, re-TURBTs reviewed uropathologist blinded information. Assessment T stage, (WHO 1973/2016), concomitant situ, histology, (TILs) necrosis (TN). grade, CIS, LVI, TN scored criteria.18 performed previously (in manuscript referred substaging).9 Briefly, single focus maximum diameter 0.5mm (ie objective observed, T1m. If >0.5 mm when T1e. either absent/sparse marked area.22 whom confirmed specimen, identifiable detrusor, analyses. After review, subgroup, AUA/SUO algorithm EAU stratification.4,8 Highest were: T1G3/HG VH, prostatic urethra involvement multifocal and/or large (?3 cm) T1G3/HG.4,8 Definitions, End Points Statistics failure. biopsy proven T1HG instillations, adequate recurring disease.4,8 Adequate consists plus ?2/3 maintenance instillations.23 Time-to-recurrence moment until occurred (BCG failure). Three-year selected because duration regimen years.4 only cytology low (LG) considered failures.4,23 Further details definitions statistical Results Study Population population consisted 535 instillations. pathology 26 cases excluded following reasons: up staging 4, downgrading G2/LG 5, 17 degraded hematoxylin tissue blocks. Of remaining 509 based specimen. Clinicopathological characteristics depicted table 1. age 67 62–71), 81% male, median 8 weeks. entire cohort 70 48–90). Table Baseline No. (%) Age (yrs): (IQR) 71 (66–77) Gender: Male 215 (81) Female 49 (19) Substaging: 72 (27) extended 192 (73) Tumor 1973): 2 6 (2) 258 (98) Smoking: 85 (32) Yes/stopped 165 (63) Missing 14 (5) Concomitant CIS: 205 (78) Yes 59 (22) focality: Unifocal 129 (49) Multifocal 132 (50) (1) size (cm): <3 51 ?3 43 (16) 170 (65) lymphocytes: 74 (28) 190 (72) necrosis: 244 (92) 20 (8) Lymphovascular invasion: 249 (94) 15 (6) Variant histology: 216 (82) Diffuse 21 Micropapillary 12 (4) Glandular (3) Squamous 4 (1.5) Neuroendocrine (0.5) Sarcamatoid Other Re-TURBT performed: 213 Risk classification start BCG: High 90 (34) 174 (66) BCG:* 27 (10) 237 (90) (6–18) completed: Yr cycles) 173 Yrs (?9 52 (20) 18 (12–24) failure:† 171 93 (35) (characteristics): first 2. T1, 3/HG 19 (7) 3. 54 Progression (MIBC, lymph node metastases): 201 (76) 63 (24) (10–48) Lymph metastases: N0 247 (93) N1-3 Distant M0 240 (91) M1 24 (9) Death last 41 (15) cause: (26) Unknown Alive 150 (57) mos (43–98) responders (55–99) 7 (5–16) Data summarized 2, substaging. Defined inductions + Specified guidelines, include recurrences, therapy. assessed tumors; present (27%) (73%). An overview main variables outcome parameters same number (79% 81%, p=0.731). administered 237/264 (90%) patients. Reasons having incorrect planning/BCG intolerance 7/264 (3%) discontinuation persistent ?T1 20/264 (8%). 93/321 developed failure; recurrence, BCG. 5–16 months). often disease: 41% p=0.002. significantly tumors: (p=0.004), (p=0.014), but (p=0.08) (fig. 1, C). p=0.005), p=0.009) 3.1, p=0.031) (HG-RFS 3; https://www.jurology.com). Main yrs 73 (64–80) (63–75) female gender (29) 28 active smoker 62 (33) 57 (79) 156 69 (96) 189 11 48 (25) 34 (47) 98 (51) 45 (23) 30 (42) 160 (83) 13 16 (21) 78 (41) 9 (13) death BC 35 (18) Figure Kaplan-Meier estimates visible detrusor A, B, PFS. C, DSS. Value determined log-rank test. Univariate Cox proportional hazard Multivariate HR (95% CI) 1.0 (0.99–1.0) 0.255 (1.0–1.1) 0.047 0.7 (0.4–1.3) 0.229 (0.3–1.6) 0.401 Smoking (active) 1.1 (0.7–1.7) 0.645 0.6 (0.3–1.1) 0.095 Pos (0.4–1.0) 0.074 (0.5–2.1) 0.977 Substage 2.2 (1.3–3.8) 0.006 3.2 (1.4–7.3) 0.005 Grade 2.3 (0.3–16) 0.409 (0.1–5.9) 0.803 1.7 (1.1–2.7) 0.015 1.8 (0.96–3.4) 0.068 Size cm 1.2 (0.6–2.4) 0.608 - 1.9 (1.3–2.9) 0.003 (0.98–3.3) 0.060 (0.7–1.9) 0.728 0.5 (0.2–1.2) 0.110 0.727 0.8 (0.4–1.5) 0.438 2.5 (1.3–4.9) 4.4 (2.1–9.4) <0.001 (0.5–2.2) 0.951 (0.7–4.5) 0.223 Understaging may occur performed. Hence, exclude possibility understaging could caused our observed association between poor outcome, 213/264 re-TURBT. (39% 18%, p=0.005). addition, (p=0.011) (p=0.028) remained contrast (p=0.12) (supplementary fig. p=0.016) 2.9, p=0.025), yet 2.8, p=0.08) confirm difference Ta central analyzed T1m/T1e disease. total, 37 down staged (T1 >Ta) (Ta >T1). similar (p=0.592), (p=0.828) (p=0.798) Importantly, favorable (both <0.01). Lastly, correlated characteristics. (OR: 6.9, <0.001) 5.0, p=0.012) 3, Interestingly, clinically unfavorable micropapillary We accuracy current end, (90, 34%) (174, 66%) subgroup. developing 2.1, p=0.001) p=0.017). no group (T1m T1e) p.adj=0.754). risk/T1m comparable (T1m/T1e) (p.adj=0.823). HR, HHR, (pooled) Recurrent Disease Very 84 ie Tis/Ta 38 46. Ta/Tis 4.1, <0.001). Within 19/46 (41%) 27/46 (59%) nonsignificant 1.8, p=0.12, (T1e-T1e) disease, statistically significant multiple testing correction (T1m-T1m; p.adj=0.19; B). 46 primary-recurrent combinations Discussion predictive improves context guidelines.4,8,17,21,24 refine likely BCG, suggesting they surveilled vigilance. previous (79 patients), 5-year RFS (29% 64%), unavailable.25 Rouprêt et al T1b below mucosae substaging).16 analysis did such VH. Moreover, selecting point, LG failures, events.4 define affect therapeutic decision making. real-world situation, performed, especially visible. Most studies investigating None 36 meta-analysis took account impact I) II) before induction, III) resection/re-TURBT specimen prevent IV) comparison disease.9,17,20,21,24,26 subanalyses investigate centralized review. Guidelines considering features, lead overtreatment line studies, rate factors.2,3,27 knowledge, demonstrate indicating sparing approach worthwhile investigating. prospective trials needed safety bladder-sparing approaches worst RCs considered. TILs. clarify frequently advanced disease.28 rarely shows inflammatory TILs.20 findings, possibly presence, specific cell subsets failure.29 limitation its retrospective design, led missing data therefore parameter Nonetheless, 110 available, HG-RFS, (data shown). unlikely misclassified size, 51/110 (46%) reported cm), far exceeds expected 18% Organization Research Treatment (EORTC) reporting bias favor tumors).3 prevalence varies considerably literature, relatively (5%).30 scoring slides, endothelial facilitate diagnosis.30 pointed towards caution cases, heterogeneity types selection bias, instead therapy.4,8 shown (using micrometers) time-consuming less substaging.10,12,21 Additionally, interobserver variability substaging.10 use, implemented every practice additional costs, reproducible 100% rate.9,10,12,15,21 Conclusions while treatments. trial safe contrast, early References : incidence mortality: trends. Eur Urol 2017; 71: 96. 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Volume 205Issue 3March 2021Page: 701-708Supplementary Advertisement Copyright Permissions© Inc.KeywordsBCG vaccineurinary neoplasmscarcinoma, transitional cellprognosisneoplasm stagingMetricsAuthor Information Expand PDF downloadLoading ...