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. 2017 Sep 18;8(49):86130-86142.
doi: 10.18632/oncotarget.20991. eCollection 2017 Oct 17.

Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in Japan: a multicenter study

Go Anan  1   2 , Shingo Hatakeyama  1 , Naoki Fujita  1 , Hiromichi Iwamura  2 , Toshikazu Tanaka  1 , Hayato Yamamoto  1 , Yuki Tobisawa  1 , Tohru Yoneyama  3 , Takahiro Yoneyama  1 , Yasuhiro Hashimoto  3 , Takuya Koie  1 , Hiroyuki Ito  4 , Kazuaki Yoshikawa  5 , Toshiaki Kawaguchi  6 , Makoto Sato  2 , Chikara Ohyama  1   3
Affiliations

Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in Japan: a multicenter study

Go Anan et al. Oncotarget. .

Abstract

Objective: Despite benefits of neoadjuvant chemotherapy (NAC), the adoption of guideline recommendations for NAC use in patients with muscle-invasive bladder cancer (MIBC) has been slow. We aimed to evaluate temporal trends in NAC use and oncological outcomes in a representative cohort of patients with MIBC.

Methods: We included 532 patients from 4 hospitals who underwent radical cystectomy (RC) for ≥ cT2 MIBC in 1996-2017. We retrospectively evaluated temporal changes in NAC use and progression-free and overall survival. Candidates for NAC were administered with either cisplatin- or carboplatin-based regimens. The impact of NAC on oncological outcomes was examined using multivariate Cox regression analysis with inverse probability of treatment weighting (IPTW) models.

Results: Of 532 patients, 336 underwent NAC followed by RC (NAC group) and 196 underwent RC alone (Ctrl group). NAC use significantly increased from 10% (1996-2004) to 83% (2005-2016). The number of patients administered with cisplatin- and carboplatin-based regimens was 43 and 280, respectively. Oncological outcomes in the NAC group were significantly improved compared to those in the Ctrl group. Multivariable analysis with IPTW models revealed that NAC significantly improved oncological outcomes in patients with MIBC. A nomogram for 5-year overall survival predicted 16% improvement in patients undergoing NAC.

Conclusions: NAC use for MIBC increased after 2005. Platinum-based NAC for MIBC potentially improves oncological outcomes.

Keywords: bladder cancer; carboplatin; cisplatin; neoadjuvant chemotherapy; trends in use.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. Trends in the use of neoadjuvant chemotherapy (NAC)
NAC use increased from 9.7% in 2004 to 96% in 2016; its use was significantly increased after 2005. Median rate of NAC use before and after 2005 were 10% and 83%, respectively (A). NAC use steadily increased between 2006 and 2011 in community hospitals, whereas it was promptly increased in the academic center in 2005 (B).
Figure 2
Figure 2. Prevalence of NAC use and the impact of chronic kidney disease (CKD) on regimens
Of 532 patients, 336 (63%) received neoadjuvant chemotherapy (NAC) followed by radical cystectomy. Most patients in the NAC group received a carboplatin-based regimen (83%). Regimens in the NAC group were gemcitabine plus carboplatin (GCarbo) in 280 (83%), gemcitabine plus cisplatin (GCis) in 43 (13%), and others in 13 (3.9%) cases (A). Of 532 patients, the number of those with and without preoperative stage 3 chronic kidney disease (CKD) was 195 (37%) and 337 (63%), respectively. Among patients with NAC, 223 of 336 (66%) did not have stage 3 CKD. Of 223 patients with NAC who did not have stage 3 CKD, 179 patients (80%) received carboplatin-based regimens (B).
Figure 3
Figure 3. Pathological and oncological outcomes
The number of pT0 and pT3-4 patients was significantly higher and lower in the NAC group than the Ctrl group, respectively (A). In addition, pathological T0 was achieved in 23% of patients. There were significant differences in progression-free (B) and overall survival (C) measures between the Ctrl and NAC groups. No statistical difference was observed between groups in progression-free (D) and overall survival (E) in the patients with stage 3 CKD.
Figure 4
Figure 4. The impact of NAC regimens on oncological outcomes
The median age for those given cisplatin- (68 years) or carboplatin-based regimens (66 years) was not statistically significant (P = 0.283) (A). The median eGFR was significantly lower in NAC patients who received carboplatin-based therapy (67 ml/min/1.73 m2) than in those who received cisplatin-based therapy (74 ml/min/1.73 m2) (B). No differences were seen in baseline characteristics between cisplatin- and carboplatin-based therapy including sex (77% vs 83%), CVD (9.3% vs 12%), and DM (23% vs 14%) except for an indication for orthotopic ileal neobladder substitution (70% vs 55%) (C). There were no significant differences between PFS (D) and OS (E) when comparing the cisplatin- and carboplatin-based therapies.
Figure 5
Figure 5. Nomogram for 5-year overall survival probability
The nomogram predicting 5-year OS showed that NAC use improved the 5-year risk of OS from 32% to 48% (a 16% improvement) in 70-year-old patients with CVD+, stage 3 CKD, cT3, cN-, and indication for orthotopic ileal neobladder substitution.
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