Phase II study of neoadjuvant chemotherapy with four cycles of dose-dense MVAC followed by radical cystectomy in Korean patients with muscle-invasive or locally advanced urothelial carcinoma of bladder.

While previous retrospective or phase II studies in Western populations showed that dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as neoadjuvant chemotherapy (NAC) was beneficial, no studies have been reported in Asian populations. This prospective phase II study aimed to evaluate efficacy and safety of ddMVAC in Korean patients with muscle-invasive bladder cancer (MIBC) or locally advanced urothelial cancer (UC). Patients with MIBC (cT2-4aN0M0) or locally advanced UC (cTanyN1-3M0) eligible for radical cystectomy (RC) were enrolled prospectively. The participants were treated with four cycles of ddMVAC with pegfilgrastim every 2 weeks. The primary endpoint was pathologic response rate (≤ypT1N0). Secondary endpoints were pathologic complete response (pCR, ypT0N0), relapse-free survival (RFS), overall survival (OS), and safety. Among 24 patients enrolled between December 2019 and August 2021, 23 were evaluable (52%, cT2-4aN0; 48%, cTanyN1-3). Eighteen patients (78%) completed four cycles of ddMVAC, while remaining five patients experienced early discontinuation. Dose modification (91%) and dose delay (70%) occurred, and the dose intensity of ddMVAC was 79%. Nineteen patients underwent RC and four patients declined. Of 19 patients who underwent RC, eight patients (42%) achieved ≤ypT1N0. With a median follow-up of 22.8 months, the median RFS was 13.5 months (95% CI, not yet evaluable) and the median OS was 28.9 months (95% confidence interval, 19.9-37.9). Our study showed substantial efficacy and safety of ddMVAC, even in patients with locally advanced UC. The ddMVAC still should be a promising option as NAC in Asian patients with UC.

Park K ，Lee HJ ，Kim TU ，Ryu H ，Ki YK ，Hong YJ ，Nam JK ... -  《-》

Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.

In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC). Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ≤ pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ≤ pT1N0M0, and we concluded this regimen was effective. High-grade (grade ≥ 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival. In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.

Choueiri TK ，Jacobus S ，Bellmunt J ，Qu A ，Appleman LJ ，Tretter C ，Bubley GJ ，Stack EC ，Signoretti S ，Walsh M ，Steele G ，Hirsch M ，Sweeney CJ ，Taplin ME ，Kibel AS ，Krajewski KM ，Kantoff PW ，Ross RW ，Rosenberg JE ... -  《-》

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy.

Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin. We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3-4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data. Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan-Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25-3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15-3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43-3.30, p <0.001) were also associated with higher risk of death. In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.

Zargar H ，Shah JB ，van Rhijn BW ，Daneshmand S ，Bivalacqua TJ ，Spiess PE ，Black PC ，Kassouf W ，Collaborators ... -  《-》

Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities.

Consensus guidelines recommend gemcitabine and cisplatin (GC) or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) as equally preferable neoadjuvant chemotherapy before cystectomy for muscle-invasive bladder cancer. This study sought to compare the ability of GC and ddMVAC to achieve pathologic response; and to evaluate the benefit of switching regimens after 1 or 2 cycles of the other. Patients aged ≥ 18 with muscle-invasive bladder cancer (≥ cT2) and who had received either GC or ddMVAC as neoadjuvant chemotherapy followed by cystectomy were retrospectively evaluated using the electronic medical record. Patients who received 1 or 2 cycles of one regimen followed by several cycles of the other regimen before cystectomy were classified as switch therapy patients. This study assessed the rates of pathologic complete response (pCR) and any degree of downstaging. Among 109 patients who received GC or ddMVAC, 7 (21%) of 33 ddMVAC patients demonstrated pCR, and 19 (25%) of 76 GC patients demonstrated pCR (odds ratio, 1.24; 95% confidence interval, 0.46-3.31; P = .67). Downstaging rates were 39% for ddMVAC and 50% for GC (P = .31). Thirty-three of 36 patients aged ≥ 70 years received GC (P < .001). Four of 7 patients treated with switch therapy showed downstaging, and 2 of 7 experienced pCR. There was no difference in pCR rates between GC and ddMVAC, and patients were most often able to receive 3 or 4 cycles of treatment. Switch therapy may be of benefit in patients whose disease has a poor initial response.

Ruplin AT ，Spengler AMZ ，Montgomery RB ，Wright JL ... -  《-》

Optimal pathological response after neoadjuvant chemotherapy for muscle-invasive bladder cancer: results from a global, multicentre collaboration.

To evaluate outcomes of patients achieving a post-treatment pathological stage of <ypT2N0 at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) to identify an optimal definition of pathological response. Patients from 10 international centres who underwent NAC for cT2-4aN0-1 MIBC and achieved <ypT2N0 disease at RC were included. The primary outcome was time to recurrence, either local or distant. Kaplan-Meier and Cox proportional hazards regression were used to evaluate associations between clinicopathological variables and outcomes. A total of 625 patients were included. The median age was 66 years and 80% were male. Gemcitabine and cisplatin (GC, 56%) and methotrexate, vinblastine, doxorubicin and cisplatin (MVAC)/dose-dense (dd)MVAC (32%) were the most common NAC regimens. ypT0, pure ypTis, ypTa ±ypTis and ypT1 ± ypTis were attained in 58.1%, 20.0%, 7.6% and 14.2% of patients, respectively. The cumulative incidence of recurrence at 5 years was 9%, 16%, 29% and 30%, respectively. Pathological stage was prognostic for recurrence, with ypTa ± Tis (hazard ratio [HR] 3.20, 95% confidence interval [CI] 1.40-7.30) and ypT1 ± Tis disease (HR 4.03, 95% CI 2.13-7.63) associated with a significantly higher recurrence risk. Pure ypTis (HR 1.66, 95% CI 0.82-3.38) and the type of NAC regimen (ddMVAC: HR 1.59, 95% CI 0.55-4.56; MVAC: HR 1.18, 9%% CI 0.25-5.54; reference: GC) were not associated with recurrence. We propose that optimal pathological response after NAC be defined as attainment of ypT0N0/ypTisN0 at RC. Patients with ypTaN0 or ypT1N0 disease (with or without Tis) at RC displayed a significantly higher risk of recurrence and may be candidates for trials investigating adjuvant therapy.

Ravi P ，Pond GR ，Diamantopoulos LN ，Su C ，Alva A ，Jain RK ，Skelton WP 4th ，Gupta S ，Tward JD ，Olson KM ，Singh P ，Grunewald CM ，Niegisch G ，Lee JL ，Gallina A ，Bandini M ，Necchi A ，Mossanen M ，McGregor BA ，Curran C ，Grivas P ，Sonpavde GP ... -  《-》