Neoadjuvant Chemotherapy Does Not Increase the Morbidity of Radical Cystectomy: A 10-year Retrospective Nationwide Study

doi:10.1016/j.euo.2018.06.014

European Urology Oncology

Volume 1, Issue 6, December 2018, Pages 525-530

https://doi.org/10.1016/j.euo.2018.06.014 Get rights and content

Abstract

Background

Neoadjuvant chemotherapy (NAC) is underutilized in the treatment of bladder cancer (BC).

Objective

To investigate the effect of NAC on the risk of surgical complications for radical cystectomy (RC) in a population-based setting.

Design, setting, and participants

All radical cystectomies performed in Finland during 2005–2014 were included in the study. Data were collected retrospectively using a web-based data collection platform. Complications were recorded for 90 d using the Clavien classification. Patients treated with NAC were compared to patients receiving RC alone using three cohorts and approaches: the entire cohort, a neoadjuvant period cohort, and a matched cohort.

Outcome measurements and statistical analysis

For all three cohorts, odds ratios (ORs) were estimated using simple binary logistic regression. In addition, a multivariable stratified logistic model with propensity score was used. For the matched cohort analysis, both univariate and adjusted analyses were carried out.

Results and limitations

During 2005–2014, 1427 RCs were performed in Finland, of which 1385 were included in the analyses. NAC was introduced in 2008, and 231 patients (16%) were assigned to NAC and 214 (15%) received two or more cycles of chemotherapy. Within 90 d, 61% of patients experienced complications and mortality was 4% (1.9% in the NAC group, and 4.4% in the RC-alone group). In simple binary logistic regression, NAC patients had significantly fewer complications, but this was not observed in multivariable or propensity score analyses. In the matched cohort analyses, no differences in complication rates could be observed. None of the analyses demonstrated higher complication rates in the NAC group.

Conclusions

Our retrospective study reports on nationwide use of NAC for BC and demonstrates that NAC does not increase RC morbidity.

Patient summary

Chemotherapy given before radical surgery does not increase severe postoperative complications in the treatment of bladder cancer.

Introduction

Bladder cancer (BC) is a common cancer, with an estimated 79 000 new cases and 17 000 cancer-related deaths in the USA in 2017 [1]. The standard treatment for patients with muscle-invasive BC is radical cystectomy (RC) with pelvic lymph node dissection (PLND) [2], [3], [4].

Surgery alone has suboptimal results in many cases. In a series of 1100 cystectomy patients, 5-yr overall survival (OS) was 58% [5]. Neoadjuvant chemotherapy (NAC) has been studied in prospective randomized trials and meta-analyses [6], [7], [8], [9], [10]. The results demonstrate an absolute OS improvement of 5%, and neoadjuvant platinum-based chemotherapy is recommended by the European Association of Urology, American Urological Association, and American Society of Clinical Oncology guidelines [2], [3], [4]. Some studies have also reported that adjuvant chemotherapy (AC) is associated with an OS benefit, but the results are conflicting [11], [12].

Despite the evidence and recommendations, and the fact that NAC use currently seems to be increasing, retrospective population-based series have shown that NAC use is lower than recommended [13], [14], [15]. The reasons for underutilization of NAC are various. First, NAC delays RC, which might compromise oncologic outcomes in chemoresistant patients [16]. However, in a Dutch national registry study, RC delay, if NAC was used, did not have a negative effect on OS [17]. Second, there is a risk of overtreatment, as clinical staging is challenging and may result in overstaging in some cases [18]. Furthermore, the survival benefit may be considered modest compared to the possible risks and toxicity related to chemotherapy. RC alone is a high-risk surgical procedure and postoperative complications are very common [19]. It has been postulated that NAC may increase RC morbidity. This issue has been investigated in three retrospective series, and none demonstrated higher morbidity among NAC patients, although all studies had significant limitations [20], [21], [22]. To verify these previous results, we carried out a nationwide study to evaluate the impact of NAC on postoperative complications.

Section snippets

Data source and content

To collect data from all 16 centers in which RCs were performed in Finland during 2005–2014, an Internet-based secure data collection platform was created. Patients were identified using ICD-10 codes (C67.*) and surgical procedure coding (Nordic Classification of Surgical Procedures) in each institution. Data were collected by urologists dedicated to BC care and each individual medical record was comprehensively examined. If possible, a urologist not responsible for performing RCs was selected

Results

The characteristics of the study population are presented in Table 1. In addition to the entire cohort divided by treatment type (RC alone vs NAC + RC), data are presented for RC patients from the neoadjuvant era and RC patients matched to NAC + RC patients. During 2005–2014, 16 centers performed 1427 RCs in Finland. Insufficient data were available for 25 patients, and these were excluded from analysis. In total, 231 patients (16%) were assigned to NAC, of whom 17 received less than two cycles

Discussion

We report here nationwide RC morbidity results over a period of decade with special emphasis on the effect of NAC treatment on complication risks. The total complication rate was 61% and mortality was 4.0% in the entire cohort. Mortality was 1.9% in the NAC + RC group and 4.4% in the RC-alone group. We performed meticulous analyses and there was no evidence suggesting that NAC would significantly increase the risk of surgical complications in patients undergoing RC for BC. No differences in

Conclusions

In this nationwide retrospective series, NAC did not increase postoperative complications after RC compared to patients treated with RC alone.

Author contributions: Antti P. Salminen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Salminen, Montoya Perez, Boström.

Acquisition of data: Salminen, Koskinen, Murtola, Vaarala, Nykopp, Seppänen, Isotalo, Marttila, Levomäki, Becker,

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The role of malnutrition universal screening tool in predicting outcomes after radical cystectomy
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The Malnutrition Universal Screening Tool integrates body mass index, unintentional weight loss and present illness to assess risk for malnutrition. The predictive role of ‘MUST’ among patients undergoing radical cystectomy is unknown. We investigated the role of ‘MUST’ in predicting postoperative outcomes and prognosis among patients after RC.
We conducted a multicenter retrospective analysis of 291 patients who underwent radical cystectomy in 6 medical centers between 2015 and 2019. Patients were stratified to risk groups according to the ‘MUST’ score [low risk (n = 242) vs. medium-to-high risk (n = 49)]. Baseline characteristics were compared between groups. Endpoints were 30-day postoperative complications rate, cancer-specific-survival and overall survival. Kaplan-Meier curves and Cox-regression analyses were used to evaluate survival and identify predictors of outcomes.
Median age of the study cohort was 69 years (IQR 63–74). Median duration of follow up for survivors was 33 months (IQR 20–43). Thirty-day major postoperative complications rate was 17%. Baseline characteristics were not different between the ‘MUST’ groups, and there was no difference in early post-operative complication rates. CSS and OS were significantly lower (p ≤ 0.02) in the medium-to-high-risk group (‘MUST’ score≥1) with estimated 3-year CSS and OS rates of 60% and 50% compared to 76% and 71% in the low-risk group, respectively. On multivariable analysis, ‘MUST’≥1 was an independent predictor of overall- (HR = 1.95, p = 0.006) and cancer-specific-mortality (HR = 1.74, p = 0.05).
High ‘MUST’ scores are associated with decreased survival in patients after radical cystectomy. Thus, the ‘MUST’ score may serve as a preoperative tool for patient selection and nutritional intervention.
Comparative study of postoperative complications after radical cystectomy during the past two decades in Japan: Radical cystectomy remains associated with significant postoperative morbidities
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Citation Excerpt :
The performance rate of NAC varied from 0 to 50% among our affiliated hospitals (data not shown). In line with our findings, several previous studies revealed that NAC was not a predictor of postoperative complications [17–19]. For example, Salminen et al. reported very similar findings that, using population data including all radical cystectomies performed in Finland from 2005 to 2014, 1,385 out of 1427 RCs were available for analyses, 16% (231/1385) were assigned to NAC, 61% (843/1385) of patients experienced complications within 90 days after surgery, and NAC did not increase RC morbidity after propensity score matching [19].
During the past 2 decades, in order to improve perioperative and oncological outcomes, a minimally invasive approach, neoadjuvant chemotherapy (NAC), and an enhanced postoperative recovery program after surgery have been introduced into routine clinical practice of radical cystectomy (RC). Our aim was to examine the differences in clinical practice and postoperative complications after RC by comparing our previous and current cohorts.
A retrospective multi-institutional study. We collected all complications within 90 days after surgery between 2011 and 2017 (current cohort), and categorized them according to a standardized methodology. Then, we compared the outcomes with those in our previous study (previous cohort, 1997–2010). A multivariate logistic regression model was utilized to determine predictors of complications in the current cohort.
A total of 838 patients were newly collected (current cohort), and 919 from the previous cohort were included in the subsequent analyses. In the current cohort, the rate of performing NAC was significantly higher (13% vs. 4%, respectively, P < 0.0001), and 26% (222/838) underwent laparoscopic RC (LRC, without robotic assistance: n = 210, with robotic assistance: n = 12). There was no significant difference in the overall complication [69% (580/838) vs. 68% (629/919), respectively, P = 0.7284] or major complication (Grades 3–5) [25% (211/838) vs. 22% (201/919), respectively, P = 0.1022] rates between the 2 cohorts. In both cohorts, the most frequent categories were infectious, gastrointestinal, wound-related, and genitourinary. In the current cohort, the performance status (odds ratio, OR = 2.11, P = 0.0013) and operative time (OR = 1.003, P = 0.0016) remained significant predictors of major complications. NAC was not associated with any or major complications.
Surgical complications related to RC still remain significant problems, despite the recent improvements in surgical techniques and perioperative care. NAC did not increase the complications.
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Pour tenir compte des variations individuelles anatomiques intrapelviennes en cas d’irradiation des tumeurs de la vessie infiltrant le muscle, la radiothérapie adaptative pourrait présenter un bénéfice dosimétrique et clinique.
Les données de dix patients pris en charge dans notre centre pour une tumeur de la vessie infiltrant le muscle par radiothérapie adaptative du “plan of the day” (PoD) individualisé ont été analysées rétrospectivement. Lors du scanner de planification, les volumes cibles et organes à risque ont été délinéés à différents taux de remplissage vésical, aboutissant à deux ou trois plans de traitement. Des imageries de positionnement ont été utilisées pour la sélection du PoD à chaque fraction. L’objectif était d’évaluer cette approche en termes de couverture du volume cible et d’épargne de dose aux tissus sains avoisinants, en la comparant à la technique de radiothérapie définie comme classique. Les objectifs secondaires concernaient la toxicité et l’efficacité.
La couverture cible était respectée avec le traitement adaptatif de97,3 % pour le volume cible anatomoclinique de la vessie (99,5 ; [60,1–100]) et 98 % pour celui de la vessie et des ganglions (98,6 ; [85,4–100]). S’agissant des organes à risque, le volume de tissu sain épargné était de 43,7 % en moyenne et le volume recevant 45 Gy (V45 Gy) de l’intestin grêle de 43,4cc (35 ; [0–129]) (contre 57,6cc). La dose délivrée dans 50 % (D50) du rectum était en moyenne de 18,7 Gy pour le traitement adaptatif (15,9 ; [2,4–44,1]) contre 17 Gy avec l’approche classique. Avec un recul médian de 2,94 ans (IC₉₅ _% [intervalle de confiance à 95 %] : 0,92-4,02), nous avons constaté trois cas de toxicité de grade 3 (30 %). Aucune toxicité de grade 4 n’a été observée. Les taux de survie globale et de survie sans progression à 2 ans étaient respectivement de 65,6 % (IC₉₅ _%: 26-87,6) et 45,7 % (IC₉₅ _%: 14,3-73).
La radiothérapie adaptative utilisant la bibliothèque de plans (PoD) a permis une réduction du volume de tissu sain irradié tout en maintenant une couverture vésicale similaire, avec une toxicité acceptable.
To account of individual intra-pelvic anatomical variations in muscle invasive bladder cancer (MIBC) irradiation, adaptive radiotherapy (ART) using a personalized plan library may have dosimetric and clinical benefits.
The data from ten patients treated for localized MIBC according to the “plan of the day” (P0oD) individualized ART technique were collected and retrospectively analysed. Target volumes and organs at risk (OAR) were delineated at different bladder fill rates, resulting in two or three treatment plans. Daily Cone-Beam CT (CBCT) was used for the selection of PoD at each fraction. Retrospectively, we delineated rectal, intestinal and target volumes on each CBCT, to assess target volume coverage and dose sparing to healthy tissues. A comparison with the conventional radiotherapy technique was performed. The secondary objectives were toxicity and efficacy.
The target coverage was respected with the adaptive treatment: 97.3% for the bladder Clinical Target Volume (CTV) (99.5; [60.1-100]) and 98% for the bladder + lymph nodes CTV (98.6; [85.4-100]). Concerning OAR, the volume of healthy tissue spared was 43.7% on average and the V45 Gy for the small bowel was 43,4cc (35; [0–129]) (versus 57,6cc). The rectal D50 was on average 18,7 Gy for the adaptive treatment (15.9; [2.4-44.1]) versus 17 Gy with the conventional approach. With a median follow-up of 2.94 years (95% CI: [0.92-4.02]), we observed three grade 3 toxicities (30%). No grade 4 toxicity was observed. The 2-year overall survival and progression-free survival rates were 65.6% (95% CI: [26-87.6]) and 45.7% (95% CI: [14.3-73]), respectively.
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Citation Excerpt :
Blood loss was even lower in the group treated with NAC. Other retrospective studies have also shown that NAC does not induce additional surgical morbidity [21]. However, not all patients benefit from NAC, and the pathological response rate ≤ pT1 was 55% in our series.
Neoadjuvant chemotherapy (NAC) is now recommended to treat muscle-invasive bladder cancer (MIBC) but is not always executed in real life. This study aims to evaluate the proportion of patients with MIBC who receive an optimal NAC, and to present the predictive factors of its achievement.
This monocenter retrospective study included all the patients who underwent radical cystectomy for ≥ pT2NxM0 MIBC between 2013, January and 2018, December. NAC consisted in 4–6 cycles of MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or 4 cycles of GC (gemcitabin, and carboplatin). Demographic (sex, age, ECOG-PS, glomerular filtration rate [GFR], and cN stage), surgical (urinary derivation, time of surgery, blood loss, and complications), and oncological characteristics were analyzed. Multivariate analysis are made to find predictors of administration of NAC.
One hundred and twenty-seven patients were included. Thirty received CNA (24%). Patients who underwent CNA were younger, with better ECOG and better GFR. Multivariate analysis showed that cN+ stage and better GFR were significantly associated to administration of NAC. Eight patients (27%) couldn’t receive an optimal treatment due to toxicity. Perioperative complication rates were similar, with or without NAC. Patients who underwent NAC had a worse GFR after treatment (−17 versus +5 mL/min, P < 0.01).
Due to the risks of toxicity, NAC can only be proposed to selected population, which is not the current patients. Immunotherapy could allow to treat more patients because of better tolerance.
3.
La chimiothérapie néoadjuvante (CNA) est recommandée dans le traitement des tumeurs de vessie infiltrant le muscle (TVIM), mais n’est pas toujours réalisée en pratique. L’objectif était d’évaluer le pourcentage de patients atteints d’une TVIM localisée recevant une CNA optimale, et d’identifier les facteurs prédictifs de sa réalisation.
Il s’agit d’une étude rétrospective, monocentrique, incluant les patients opérés d’une cystectomie pour TVIM localisée entre janvier 2013 et décembre 2018. La CNA consistait en 4 à 6 cures de MVAC intensifié (méthotrexate, vinblastine, doxorubicine, et cisplatine) ou de GC (gemcitabine, et cisplatine). Les caractéristiques démographiques (sexe, âge, ECOG-PS, débit de filtration glomérulaire [DFG], et stade cN), chirurgicales (dérivation urinaire, durée opératoire, pertes sanguines, et complications périopératoires) et carcinologiques étaient analysées. Les facteurs prédictifs d’administration de la CNA étaient recherchés en analyse multivariée.
Cent-vingt-sept patients ont été inclus, dont 30 ont reçu une CNA (24 %). Les patients traités par CNA étaient plus jeunes, avec un meilleur ECOG et un meilleur DFG. En analyse multivariée, le statut ganglionnaire cN+ et un meilleur DFG étaient significativement associés à la probabilité d’avoir une CNA. Huit patients (27 %) n’ont pas pu recevoir la totalité du traitement pour toxicité. Le taux de complications périopératoires était similaire avec ou sans CNA. Les patients traités par CNA avaient une diminution plus importante de leur DFG (−17 versus +5 mL/min, p < 0,01).
En raison du risque de toxicité, la CNA ne peut être proposée qu’à une population sélectionnée. Cela ne correspond pas aux patients rencontrés en pratique courante. Les immunothérapies pourraient permettre de traiter plus de patients.
3.
Reply to Francesco Montorsi, Marco Bandini, and Andrea Necchi's Letter to the Editor re: Malte W. Vetterlein, Jakob Klemm, Philipp Gild, et al. Improving Estimates of Perioperative Morbidity After Radical Cystectomy Using the European Association of Urology Quality Criteria for Standardized Reporting and Introducing the Comprehensive Complication Index. Eur Urol 2020;77:55–65: Assessing the Morbidity of Multimodal Approaches in Patients with Muscle-invasive Bladder Cancer
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Surgical Safety of Radical Cystectomy and Pelvic Lymph Node Dissection Following Neoadjuvant Pembrolizumab in Patients with Bladder Cancer: Prospective Assessment of Perioperative Outcomes from the PURE-01 Trial
2020, European Urology
No data are available on the surgical safety of radical cystectomy (RC) and pelvic lymph node dissection (PLND) after the administration of checkpoint inhibitors. We aimed at reporting the first prospective rigorous assessment of perioperative outcomes after RC and extended PLND following neoadjuvant pembrolizumab in a contemporary cohort of patients with muscle-invasive bladder cancer (MIBC) enrolled in the PURE-01 trial. From February 2017 to June 2019, a total of 68 consecutive patients who received three courses of 200 mg pembrolizumab intravenously every 3 wk and were subsequently treated with either open or robot-assisted RC and PLND at a single high-volume tertiary referral center were identified. All men had prospectively collected data about intra- and postoperative outcomes. Postoperative complications were graded according to the Clavien-Dindo system. Perioperative data were prospectively and systematically collected during patient interviews at 90 d after surgery according to the European Association of Urology (EAU) Guidelines Panel recommendations on reporting and grading complications. Overall, 52 (77%) versus 16 (23%) patients underwent robot-assisted versus open RC, and 31 patients (46%) received an orthotopic neobladder. Median blood loss and length of stay were 150 ml and 12 d, respectively. Overall, 52 (77%), 47 (69%), and 22 (32%) patients experienced any-grade complications, grade ≥2 complications, and readmission at 90 d, respectively. High-grade complications (defined as Clavien-Dindo ≥3a) were observed in 23 patients (34%). The most frequent complications were fever (n = 35, 52%) and ileus (n = 21, 31%). None of the patients experienced perioperative mortality at 90 d. Our data represent the first prospective evidence supporting the surgical safety of RC and PLND in patients with N0M0 MIBC who received neoadjuvant immunotherapy with pembrolizumab.
The current study represents the first prospective evidence supporting the surgical safety of radical cystectomy and pelvic lymph node dissection in patients with nonmetastatic bladder cancer who received neoadjuvant immunotherapy with pembrolizumab.

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Neoadjuvant Chemotherapy Does Not Increase the Morbidity of Radical Cystectomy: A 10-year Retrospective Nationwide Study

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Data source and content

Results

Discussion

Conclusions

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