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Randomized phase III trial of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin, or gemcitabine and cisplatin as perioperative chemotherapy for patients with muscle-invasive bladder cancer. Analysis of the GETUG/AFU V05 VESPER trial secondary endpoints: Chemotherapy toxicity and pathological responses

  • Christian Pfister,
  • Gwenaelle Gravis,
  • Aude Fléchon,
  • Michel Soulié,
  • Laurent Guy,
  • Brigitte Laguerre,
  • Nicolas Mottet,
  • Florence Joly,
  • Yves Allory,
  • Valentin Harter,
  • Stéphane Culine,
  • the VESPER Trial Investigators

Background

Perioperative chemotherapy (neoadjuvant or adjuvant) has been developed to increase overall survival for nonmetastatic muscle-invasive bladder cancer (MIBC). Retrospective studies or prospective phase II trials have been reported to use dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). As dd-MVAC has shown higher response rates in metastatic disease, better efficacy is expected in the perioperative setting.

Objective

We designed a randomized phase III trial to compare the efficacy of dd-MVAC or GC in MIBC perioperative (neoadjuvant or adjuvant) setting.

Design, setting and participants

A total of 500 patients were randomized from February 2013 to March 2018 in 28 centers and received either six cycles of dd-MVAC every 2 wk or four cycles of GC every 3 wk.

Outcome measurements and statistical analysis

The primary endpoint (progression-free survival at 3 yr) was not reported. We focused on secondary endpoints: chemotherapy toxicity and pathological responses.

Results and limitations

In the neoadjuvant group, 218 patients received dd-MVAC and 219 received GC. Of the patients, 60% received six cycles in the dd-MVAC arm and 84% received four cycles in the GC arm; 199 (91%) and 198 (90%) patients underwent surgery, respectively. Complete pathological response (ypT0pN0) was observed in 84 (42%) and 71 (36%) patients, respectively (p = 0.2). An organ-confined status (<ypT3pN0) was obtained in 154 (77%) and 124 (63%) patients, respectively (p = 0.001). In the adjuvant group, 40% of patients received six cycles in the dd-MVAC arm and 60% received four cycles in the GC arm. Most of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3 toxicities concerned hematological toxicities, reported for 129 (52%) patients in the dd-MVAC group and 134 (55%) patients in the GC group. Gastrointestinal (GI) grade ≥3 disorders were more frequently observed in the dd-MVAC arm (p = 0.003), as well as asthenia of grade ≥3 (p < 0.001).

Conclusions

The toxicity of dd-MVAC was manageable with more severe asthenia and GI side effects than that of GC in perioperative chemotherapy. A higher local control rate (complete pathological response, tumor downstaging, or organ confined) was observed in the dd-MVAC arm (p = 0.021). However, such data have to be confirmed on progression-free survival, with primary endpoint data expected in mid-2021.

Commented by Dr. Benjamin Pradere

Pfister et al published this month in European Urology the first results of the awaited VESPER trial. After the presentation of the preliminary results during the ASCO GU 2020, the article reporting the secondary endpoints of the study has been published. Indeed, as the primary endpoint, the progression free survival at three years is not yet mature, the authors reported the secondary endpoints, which include chemotherapy toxicity and pathological responses.

This French Phase 3 randomized trial compared the two main regimens used for perioperative (neoadjuvant and adjuvant) chemotherapy in MIBC: dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) or gemcitabine and cisplatin (GC). The study design is represented in Figure 1.

Figure 1: VESPER study design

The study enrolled 500 patients with MIBC ≥pT2N0M0 (variants were accepted if there were combined with classical urothelial carcinoma). Patients in the GC arm received 4 cycles (gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1, every 3 weeks) and patients in the dd-MVAC arm (methotrexate 30 mg/m2 on day 1, vinblastine 3 mg/m2 on day 2, doxorubicin 30 mg/m2 on day 2, and cisplatin 70mg/m2 on day 2 with associated granulocyte colony-stimulating factor (G-CSF) from day 3 to day 9, every 2 weeks). The cisplatin dose was adapted to renal function for the GC group and the dd-MVAC group.

Concerning patient receiving neoadjuvant chemotherapy (n=437), 39% of the patients received fewer than 6 cycles in the dd-MVAC arm and 16% received less than 4 cycles in the GC arm. In the adjuvant group (n=56) 60% of the patients in the dd-MVAC arm received less than 6 cycles whereas only 19% received less than 4 cycles in the GC arm.

Most CTACE Grade ≥3 were hematological toxicities, with more severe anemia in the dd-MVAC group (p<0.001). Nonhematological toxicities ≥3 are presented in the table 1.

Table 1: CTCAE grade ≥3 non-hematological toxicities reported for patients of the dd-MVAC and GC arms

The other secondary endpoint was the pathological response on the radical cystectomy specimen. There was no difference in terms of complete response (ypT0pN0) between groups. Nevertheless, the authors used other criteria to assess the pathological response: the local control rate which included complete pathological response, tumor downstaging or organ confined. With this definition the dd-MVAC regimen showed a higher local control compared to the GC arm (Table 2). One of the reasons for this result argue by the authors is fewer advanced stages and/or greater number of chemotherapy cycles.

One interesting and important result from the study is the difficulty to perform adjuvant chemotherapy especially a six-cycles planned dd-MVAC schedule, which wasn’t reached in up to 60% of the cases. These results continue to support the use of NAC as often as possible for MIBC.

Finally, as toxicity of the dd-MVAC arm was manageable (despite more severe asthenia and GI side effects) and as there was a higher local control rate (complete pathological response, tumor down- staging, or organ confined) observed for the dd-MVAC schedule, this regimen seems a good option. Nevertheless, results in terms of clinical oncological outcomes (3-yr PFS) are still awaited and we are impatient to get the results probably in mid-2021.