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- Publisher
- Wolters Kluwer Health
- Copyright
- Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc.
- ISSN
- 1661-7657
- eISSN
- 1661-7657
- DOI
- 10.1097/cu9.0000000000000099
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- See Article on Publisher Site
Abstract
Background: Compliance with the guideline recommendations for neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is incomplete. The adjuvant chemotherapy approach has the advantage of pathology-based decision-making, allowing for pa- tient selection. In addition, radical surgery is not delayed and treatment-related toxicity does not impair surgical fitness. The proportion of patients who completed chemotherapy after cystectomy among those who were fit and in need of treatment were evaluated. The rea- sons for not completing adjuvant chemotherapy were determined. Materials and methods: We retrospectively evaluated all patients who had undergone radical cystectomy at our center over the last 7 years. Indications for adjuvant chemotherapy included pathological T > 2, any node+, or surgical margin involvement. Only patients who were fit for chemotherapy before surgery were included in the study. Results: Of the 52 patients with muscle-invasive bladder cancer, 14 received neoadjuvant chemotherapy or unfit for chemotherapy were excluded. Of the remaining 38 patients, 14 (37%) had bladder-confined cancers and did not require additional chemotherapy. Of the 24 patients who needed chemotherapy and were fit to receive it, 8 patients completed treatment (33%), and 3 discontinued treatment due to toxicity. Twelve patients (50%) declined chemotherapy, whereas 1 patient became unfit for chemotherapy after surgery. Conclusions: While the adjuvant chemotherapy approach could save unnecessary treatment in 37% of patients, two-thirds of those who needed chemotherapy did not complete it. Patient refusal was the primary reason for not receiving treatment. Keywords: Adjuvant chemotherapy; Muscle-invasive bladder cancer; Neoadjuvant chemotherapy 1. Introduction be associated with significant morbidity, rendering some frail patients unfit for subsequent chemotherapy. The magnitude of this effect is im- The current urological guidelines recommend neoadjuvant chemother- portant because if ineligibility for adjuvant chemotherapy after apy before radical cystectomy for all patients with muscle-invasive blad- cystectomy is common, a significant proportion of patients requiring [1–3] der cancer (MIBC). These recommendations stem from random- chemotherapy would receive suboptimal management if treated with ized trials showing a 5%–7% overall survival benefit in patients initial cystectomy as opposed to neoadjuvant chemotherapy. In this who received systemic chemotherapy before radical cystectomy ver- particular case, the potential benefits of avoiding unnecessary treat- [4–7] sus cystectomy alone. Despite the survival advantage of neoad- ment in a fraction of patients may be outweighed by the disadvantage juvant chemotherapy in patients with MIBC, there is only partial of not providing chemotherapy to those who require it. compliance with the guidelines, as many urologists initially offer Our study primarily aimed to determine the percentage of pa- radical cystectomy and decide on adjuvant therapy based on the fi- tients who received adjuvant chemotherapy among those who [8,9] nal pathology report. Arguments supporting initial radical were fit and had absolute indications for such treatment. We then cystectomy include treatment-related toxicity and delay in surgery, clarified why the patients were not treated. especially among patients who are nonresponders to neoadjuvant [10] therapy. In addition, up to 25% of patients with MIBC whose cancer is confined to the bladder can be cured with cystectomy 2. Materials and methods [11,12] alone, and additional chemotherapy may be unnecessary. An important argument against initial cystectomy is that surgery may Medical charts of patients who underwent radical cystectomy for MIBC at our medical center between January 2013 and April 2020 were reviewed. In this study, absolute indications for adju- *Corresponding Author: Roy Croock, 35 Engel Apt 14, Kfar Sava, 44653, Israel. E-mail address: croock20@gmail.com (R. Croock). vant chemotherapy were based on the final pathology and included Current Urology, (2023) 17, 2, 109–112 any pathological T > 2, any N > 0, or positive surgical margins. Pa- Received November 28, 2020; Accepted March 3, 2021. tients without MIBC and those who received neoadjuvant chemo- http://dx.doi.org/10.1097/CU9.0000000000000099 therapy were excluded. Adjuvant chemotherapy consisted of 4 2 2 Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. This is courses of cisplatin (70 mg/m ) and gemcitabine (1250 mg/m ). Pa- an open access article distributed under the terms of the Creative Commons tients who completed fewer than 3 courses of adjuvant therapy Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it were defined as “not treated.” is permissible to download and share the work provided it is properly cited. The The Charlson Comorbidity Index scores and 6-week postopera- work cannot be changed in any way or used commercially without permission from the journal. tive kidney function (glomerular filtration rate, mL/min) were 109 Croock et al. Volume 17 Issue 2 2023 www.currurol.org documented. Patient eligibility for systemic chemotherapy before All patients, excluding one who was fit for chemotherapy prior and 6 weeks after radical cystectomy was determined. Contraindi- to cystectomy, remained fit for such treatment after surgery. cations to chemotherapy (patients unfit for chemotherapy) in- cluded a glomerular filtration rate <60mL/min, or poor performance status (European Collaboration Oncology Group score >2), significant 4. Discussion coronary artery disease, or heart failure (NYHA class III). Patients who were considered fit for chemotherapy before surgery but developed one The combination of radical cystectomy with systemic chemotherapy or more contraindications for chemotherapy 6 weeks after cystectomy offers a 5%–7% overall survival benefit as opposed to cystectomy [4–7] were considered to have converted to being unfit as a result of the initial alone among patients with MIBC. Unfortunately, when com- cystectomy. The proportion of patients with MIBC who received adju- pared with the literature on neoadjuvant chemotherapy, few studies vant chemotherapy among those who required such therapy based on have assessed the impact of adjuvant chemotherapy postcystectomy, their final pathology report and were defined as fit for chemotherapy and most were not randomized controlled trials. Sternberg et al. re- before surgery was determined. Patients who were unfit for chemother- ported a 7% progression-free survival benefit with adjuvant therapy [13] apy before cystectomy were excluded. In our study, all patients received as opposed to surgery alone, whereas other studies suggest that neoadjuvant chemotherapy prior to cystectomy per the guideline med- adjuvant therapy is superior to neoadjuvant therapy among patients [14] icine; however, only 8 among 46 eligible patients (17%) agreed. Among with positive lymph nodes. those in whom adjuvant chemotherapy was indicated but not received, Although the combination of radical cystectomy with systemic the reasons for them not being treated were elucidated. chemotherapy has been extensively studied, in most studies, the combination has been compared with that of radical cystectomy alone. Therefore, despite the clear benefits of combination therapy, 3. Results it is uncertain whether chemotherapy should be administered be- fore or after cystectomy. Urological guidelines support upfront Sixty-four patients underwent radical cystectomy for urothelial chemotherapy before rather than after surgery, although there is cancer during the study period at our medical center. Of these, little direct evidence supporting this choice of treatment timing. A 52 had MIBC, and 12 underwent early cystectomy for high-risk single randomized trial directly compared adjuvant versus neoad- non- MIBC. Eight patients who received neoadjuvant chemo- juvant chemotherapy but failed to show an advantage over any ap- [15] therapy were excluded from the study. Six patients were ineligi- proach. Therefore, it is conceivable that the addition of systemic ble for chemotherapy before cystectomy and were excluded chemotherapy indeed improves outcomes; however, its timing is of from the analysis. The remaining 38 patients were included as less importance. the study participants (Fig. 1). On the basis of the final pathol- One significant justification for adjuvant therapy over neoadju- ogy report, 14 patients (37%) had bladder-confined cancer vant therapy is that a significant percentage of patients with MIBC [12,13] (pT2N0M0R0) and did not require adjuvant chemotherapy. may be cured by radical cystectomy alone, thus precluding Of the remaining 24 patients who were both fit for and required the need for exposure to toxic chemotherapy in this patient subset. treatment, 11 (46%) received any number of courses of adju- This may have contributed to the patient’s decision not to receive vant chemotherapy; however, only 8 patients completed three neoadjuvant therapy, although the patients’ reasoning remains un- or more courses of chemotherapy (Table 1). Three patients clear. However, not all patients receiving combination therapy discontinued the therapy because of neutropenic fever, elevated with adjuvant chemotherapy after cystectomy will complete their creatinine levels, and cognitive impairment. treatment plan. Factors such as postoperative morbidity or patient Figure 1. Patient flow chart. MIBC = muscle invasive bladder cancer.* Eight patients completed therapy, three patients discontinued treatment. 110 Croock et al. Volume 17 Issue 2 2023 www.currurol.org Table 1 Clinical and pathological data of the 24 patients who were fit for chemotherapy and had indications to receive such treatment. Did not receive chemotherapy Received chemotherapy p Total patients, n 13 11 Age (median), yr 67 70.5 0.21 Gender 0.8 Male 11 11 Female 2 0 Final pathology 0.85 T3+ 10 5 Node + 1 0 T3+, node + 2 6 Completed 3+ courses of adjuvant chemotherapy NA 8 (73%) Charlson Comorbidity Index score 0.75 <3 5 3 3–45 7 >4 3 1 Ileal conduit 12 10 Neo-bladder 1 1 choice may preclude preplanned chemotherapy and deprive patients Acknowledgments of optimal oncologic treatment. Our results showed that 54% of pa- tients eligible for and requiring adjuvant therapy based on the final None. pathology results (pT3, N+, or R+) did not receive any chemother- apy after surgery. In addition, a few patients experienced toxicity Statement of ethics from chemotherapy after cystectomy, rendering them unable to complete therapy. As a result, the proportion of patients who completed dual ther- This study received Helsinki approval study number 0092-19- KMC. apy among those who were fit and needed it was 33% in our report. According to the institutional regulations, this study did not re- The dominant reason for not receiving adjuvant chemotherapy quire patient consent or institutional review board approval, for in whom it was indicated and could have received it was patient re- it was a retrospective study based on patients’ medical files only. fusal, whereas surgical morbidity, rendering patients unfit for ad- juvant treatment, occurred in a single patient. These findings imply Conflict of interest statements that although initial cystectomy is well tolerated by most patients and offers a favorable pathology in 37% of cases, it is associated The authors declare no conflicts of interest. with failure to administer chemotherapy in 66% of patients requir- ing treatment primarily due to patient choice and not related to pa- Funding source tient fitness or complications from surgery. The limitations of our study are related to its retrospective design and None. small sample size, which ultimately limit our ability to develop a stan- dard treatment regimen for this patient population. Additionally, pa- Author contributions tients’ choices may reflect local feelings and beliefs that are not necessar- ily inferable elsewhere. Furthermore, patient compliance to neoadjuvant All authors contributed equally in this study. chemotherapy was not assessed. Nevertheless, our results are significant in showing that more patients are harmed when surgery is performed References initially than in those who benefit from avoiding unnecessary chemo- [1] Available at: https://uroweb.org/guideline/bladder-cancer-muscle-invasive- therapy, as these patients tend to decline adjuvant chemotherapy despite and-metastatic/. Accessed November 2020. the absolute indications for treatment. Improved patient compliance [2] Available at: https://www.auanet.org/guidelines/bladder-cancer-non- may be achieved if a neoadjuvant approach is adopted. metastatic-muscle-invasive-guideline. Accessed November 2020. [3] Available at: https://www.nccn.org/professionals/physician_gls/pdf/blad der_blocks.pdf. Accessed November 2020. 5. Conclusions [4] Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349(9):859–866. Our findings show that half of the patients who required chemo- [5] Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for therapy after radical cystectomy declined such treatment. Becom- muscle-invasive bladder cancer: A randomised controlled trial. International ing physically unfit for postoperative chemotherapy secondary to collaboration of trialists. Lancet 1999;354 (9178):533–540. surgery is uncommon. When considering all reasons for not com- [6] International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute pleting chemotherapy, only a third of the patients who needed it Bladder Cancer Clinical Studies Group); European Organisation for Research and were fit for treatment actually completed the entire treatment and Treatment of Cancer Genito-Urinary Tract Cancer GroupInternational plan. These results suggest that adopting a neoadjuvant chemo- phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine therapy approach could improve the proportion of patients with chemotherapy for muscle-invasive bladder cancer: Long-term results of the MIBC receiving dual-modality treatment. BA06 30894 trial. J Clin Oncol 2011; 29(16):2171–2177. 111 Croock et al. Volume 17 Issue 2 2023 www.currurol.org [7] Sherif A, Holmberg L, Rintala E, et al. Neoadjuvant cisplatinum based [13] Sternberg CN, Skoneczna I, Kerst JM, et al. Immediate versus deferred combination chemotherapy in patients with invasive bladder cancer: A chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ combined analysis of two Nordic studies. Eur Urol 2004; 45(3):297–303. M0 urothelial carcinoma of the bladder (EORTC 30994): An intergroup, [8] Macleod LC, Yabes JG, Yu M, et al. Trends and appropriateness of open-label, randomised phase 3 trial. 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Clin Genitourin Cancer 2014; 12(5):e233–e240. [11] May M, Helke C, Nitzke T, Vogler H, Hoschke B. Survival rates after radical cystectomy according to tumor stage of bladder carcinoma at first How to cite this article: Croock R, Modai J, Avda Y, Shpunt I, Jaber M, presentation. Urol Int 2004; 72(2):103–111. Peretz Y, Shilo Y, Leibovici D. Adjuvant chemotherapy after radical [12] Mazzone E, Knipper S, Mistretta FA, et al. Is neoadjuvant chemotherapy cystectomy: Do all patients who need chemotherapy after surgery ac- for pT2 bladder cancer associated with a survival benefit in a tually receive it? Curr Urol 2023;17(2):109–112. doi: 10.1097/CU9. populationbased analysis? Cancer Epidemiol 2019; 58:83–88. 0000000000000099
Journal
Current Urology – Wolters Kluwer Health
Published: Jun 2, 2023