VESPER study: dd-MVAC neoadjuvant chemotherapy significantly improves 3-year PFS in non-metastatic muscle-invasive bladder cancer

Introduction Bladder cancer is the second most common cancer of the urinary system after prostate cancer, and about 2.
7 million people worldwide are diagnosed with bladder cancer every year
.

Radical cystectomy is the standard of care for patients with nonmetastatic muscle-invasive bladder cancer (MIBC)
.

Neoadjuvant chemotherapy (NAC) is currently recommended for MIBC, resulting in a 5% absolute benefit in overall survival (OS)
.

However, the optimal treatment regimen remains to be discussed
.

Previous studies have shown better local control outcomes with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) for MIBC neoadjuvant chemotherapy
.

The researchers designed a randomized phase III controlled study to observe the difference in the efficacy of dd-MVAC versus gemcitabine + cisplatin (GC) in patients requiring chemotherapy before or after radical cystectomy
.

The findings were published in the Journal of Clinical Oncology
.

Methods: Inclusion criteria: primary bladder tumor; histologically confirmed muscle-invasive urothelial carcinoma (with typical urothelial carcinoma acceptable); patients treated with NAC with tumor stage cT2, cT3, or cT4a N0 M0 stage; tumor stage pT3 or pT4 or pTN+ or M0 regardless of pT in patients receiving adjuvant chemotherapy; no prior chemotherapy; creatinine clearance ≥50 mL/min (Cockcroft‑Gault formula)
.

Exclusion criteria were pure adenocarcinoma, pure squamous cell carcinoma, mixed or pure small cell neuroendocrine carcinoma; ventricular ejection fraction <50%; history of cancer in the past 5 years; pregnant woman or currently breastfeeding; patient age >80 years
.

Chemotherapy regimen dd-MVAC group: methotrexate 30mg/m2 once on day 1; vinblastine 3mg/m2 once, doxorubicin 30mg/m2 once, and cisplatin 70mg/m2 once on day 3; On the 9th day, the corresponding granulocyte colony-stimulating factor was used, once every 2 weeks, for a total of 6 courses; GC group: gemcitabine 1250mg/m2 once on the 1st and 8th day, cisplatin 70mg/m2 on the 1st day 1 times, once every 3 weeks, for a total of 4 courses of treatment
.

In clinical practice, NAC is rarely used, so adjuvant therapy was included in this study
.

The primary endpoint of the study was 3-year progression-free survival (PFS), defined as the time to detection of bladder tumor progression or patient death within 3 years
.

Secondary endpoints were chemotherapy toxicity and response rate (RR)
.

The study also analyzed the safety of NAC, including postoperative complications and time to progression (TTP) in cystectomy patients
.

OS was defined as the time from the patient's last follow-up to death
.

Results: The study included 500 patients from 28 research centers from February 2013 to March 2018, and 7 patients were finally excluded (see Figure 1 for the process flow)
.

The baseline conditions of patients in different chemotherapy regimen groups are shown in Table 1
.

Figure 1 Flow chart of the trial protocolTable 1 Baseline pathological remission of patients in different chemotherapy groups remission (P=0.
2)
.

But the dd-MVAC group had better local control rate (P=0.
021)
.

The 3-year PFS was higher in the PFSDd-MVAC group (3-year PFS rate: 64% vs 56%, HR = 0.
77 [95% Cl, 0.
57-1.
02], P = 0.
066) (see Figure 2)
.

Multivariate analysis (COX proportional hazards regression) was performed on the 3-year PFS to calculate the adjusted HR
.

The results showed that HR of the treatment groups differed significantly by chemotherapy regimen, suggesting that adjuvant chemotherapy and NAC should not be used in combination (Table 2)
.

To better illustrate the NAC results, which are presented separately (Fig.
2B), 3-year PFS was significantly improved in patients who received NAC (3-year PFS rate: 66% vs 56%, HR = 0.
70 [95% Cl, 0.
51-0.
96], P=0.
025)
.

Figure 2 Kaplan-Meier curve of 3-year PFS in the two chemotherapy regimens Table 2 Safety of COX proportional hazards regression model for 3-year PFS There were 129 cases (52%) of ≥ grade 3 hematological adverse events in the dd-MVAC group, and 129 cases (52%) in the GC group 134 cases (55%, P<0.
001)
.

Debilitating symptoms occurred in 14% of patients in the dd-MVAC group compared with 4.
1% in the CG group (P<0.
001)
.

Gastrointestinal reactions of grade 3 and above, including nausea and vomiting, were observed in the dd-MVAC group
.

There were 16 early surgery-related complications (during the first month) in the GC group and 12 in the dd-MVAC group
.

In contrast, there were 4 late complications (1-3 months) in the GC group and 5 in the dd-MVAC group (see Table 3)
.

The GC group (20 cases) had more severe postoperative complications than the dd-MVAC group (14 cases)
.

Table 3.
Other secondary endpoints of major surgery-related complications showed significantly longer TPP in the dd-MVAC group (3-year PFS rate: 69% vs 58%, HR=0.
68 [95% CI, 0.
50-0.
93] , P=0.
014; see Figure 3)
.

The difference in TPP was more pronounced in the NAC-treated group (3-year PFS rate: 71% vs 59%, HR=0.
62 [95% CI, 0.
44-0.
85], P=0.
005)
.

Figure 3.
Kaplan-Meier curves for 3-year TPP.
More detailed analysis of OS data will be performed after 5 years of follow-up
.

The currently monitored data (median follow-up 40 months) showed better outcomes in the dd-MVAC group (HR=0.
74 [95% CI, 0.
47-0.
92], see Figure 4)
.

Figure 4 Summary of estimates of OS data The VESPER trial was a landmark study in the history of MIBC chemotherapy
.

Three-year PFS improved in the dd‑MVAC arm, but the study did not meet the primary endpoint
.

In the population receiving NAC, the 3-year PFS was significantly better, suggesting that the dd‑MVAC regimen is superior and should be an appropriate treatment option for MIBC patients
.

Final data on OS are expected to confirm these results and guide the design of future trials of chemotherapy combined with immunotherapy
.

Reference: Christian Pfister et, al.
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial.
Journal of Clinical Oncology.
2022 Mar 7; JCO2102051.
doi: 10.
1200/JCO.
21.
02051 Revision: XY Editor: LR Execution: LR