The relative safety and effectiveness of the two commonly-used chemotherapy regimens, gemcitabine and cisplatin (GC) and dose-dense MVAC (dd-MVAC), is currently unknown, although retrospective data2 and data from response rates in the metastatic setting suggest a superiority of the dd-MVAC regimen.
During the session on Risk Stratification and Management of High-Risk Muscle Invasive Urothelial Carcinoma, Dr. Stephane Culine presented preliminary results of the GETUG/AFU V05 VESPER trial which seeks to answer these questions.
In this trial, patients who were planned to undergo either neoadjuvant or adjuvant chemotherapy in one of 28 French centers were randomized to receive either GC every three weeks for four cycles or dd-MVAC every two weeks for six cycles. Three-year progression-free survival was chosen as the primary endpoint, and the trial was powered to show 10% superiority in this endpoint in patients receiving dd-MVAC over those receiving GC. Overall survival, pathologic response at the time of cystectomy (in the neoadjuvant arm), and toxicity were secondary endpoints.
In this presentation of interim results, Dr. Culine discussed the study findings with regard to pathologic outcomes in the neoadjuvant group as well as the tolerability and toxicity results in all recruited patients. Survival results are still pending.
Enrollment started in February 2013 and was completed in March 2018. 437 patients undergoing neoadjuvant chemotherapy were recruited. 218 were randomized to receive dd-MVAC and 219 were randomized to GC. Significantly fewer patients were recruited to the adjuvant arm, 56, which is unsurprising given that most patients who can receive neoadjuvant chemo should do so under the current standard of care.
With regards to toxicity and tolerability, 60% of patients in the neoadjuvant dd-MVAC arm received all six cycles (11% 5 cycles, 14% 4 cycles) while 84% in the neoadjuvant GC arm received all four planned cycles. A similar difference was also seen in the patients undergoing adjuvant chemotherapy, with 40% and 60% completing all preplanned therapies respectively. The majority of grade ≥ 3 toxicities were hematologic, with 50% and 54% suffering grade ≥ 3 hematologic toxicity, which was not significantly different. There were, however, significantly more grade ≥ 3 GI (3% vs 10%, p=0.003) and asthenic (4% vs 14%, p=0.0002) adverse events in the dd-MVAC group. Three patients died while undergoing chemotherapy in the dd-MVAC arm while one died in the GC arm.
Despite this signal of increased toxicity in the dd-MVAC group, there was no difference in the proportion of patients who went on to undergo cystectomy, which was 91% and 90% in the dd-MVAC and GC groups respectively. Also, despite the increased early cessation of chemotherapy in the dd-MVAC arm, pathologic responses in the neoadjuvant patients in this arm were superior. 42% vs 36% (p=0.02) demonstrated complete pathologic response (ypT0N0) at the time of cystectomy. 77% vs 63% were found to have an organ-confined disease (<ypT3N0) at the time of cystectomy.
These results confirm the popularly understood contrast between these two regimens, with dd-MVAC showing signals of greater efficacy but also greater toxicity. Final results of GETUG/AFU V05 VESPER will be eagerly awaited in 2021 to finally determine whether dd-MVAC indeed delivers improved overall survival and whether that improvement is worth the cost of increased toxicity which has been appreciated so far.
Presented by: Stephane Culine, MD, PhD, Medical Oncology, Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris, Paris, France
Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia Pennsylvania, Twitter: @mcstroth at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California
References:
1. Sternberg, Cora N., Iwona Skoneczna, J. Martijn Kerst, Peter Albers, Sophie D. Fossa, Mads Agerbaek, Herlinde Dumez et al. "Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3–pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial." The lancet oncology 16, no. 1 (2015): 76-86.
2. Zargar, Homayoun, Jay B. Shah, Bas W. Van Rhijn, Siamak Daneshmand, Trinity J. Bivalacqua, Philippe E. Spiess, Peter C. Black, and Wassim Kassouf. "Neoadjuvant dose dense MVAC versus gemcitabine and cisplatin in patients with cT3-4aN0M0 bladder cancer treated with radical cystectomy." The Journal of urology 199, no. 6 (2018): 1452-1458.