Implications for Efficacy and Safety of Total Dose and Dose-Intensity of Neoadjuvant Gemcitabine-Cisplatin in Muscle-Invasive Bladder Cancer: Three-Week Versus Four-Week Regimen

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). METHODS: Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and < pT2N0). RESULTS: A total of 251 patients were treated with GC-4w and 455 with GC-3w. pT0N0 was significantly higher for patients treated with GC-3w compared to GC-4w, 46% versus 32% (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI] 1.16–2.80; P = 0.009); and for < pT2N0 60% versus 47% (aOR 1.08; 95% CI 0.70–1.66; P = 0.743). There were no significant differences between GC-4w and GC-3w regarding survival parameters. GC-3w patients discontinued treatment more frequently and showed a higher degree of neutropenia. CONCLUSIONS: A significantly higher complete response-rate was observed in the patient group treated with the more cisplatin-dose-intense 3-week schedule. The side-effect profile was in favor of the 4-week approach while relapse-free and overall survival were similar.

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Early outcomes with neoadjuvant high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (HD-MVAC) or gemcitabine and cisplatin (GC) in muscle-invasive urothelial carcinoma of the bladder: A single-institution experience.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.7_suppl.280 ◽

2011 ◽

Vol 29 (7_suppl) ◽

pp. 280-280 ◽

Cited By ~ 1

Author(s):

N. Mitra ◽

J. P. Monk ◽

K. S. Pohar ◽

A. Shabsigh ◽

D. S. Sharp ◽

...

Keyword(s):

Bladder Cancer ◽

Dose Intensity ◽

Complete Response ◽

Invasive Bladder Cancer ◽

High Dose ◽

Muscle Invasive Bladder Cancer ◽

Carcinoma Of The Bladder ◽

Muscle Invasive ◽

Median Interval

280 Background: Compared to MVAC, HD-MVAC achieves significantly higher complete response rates in patients (pts) with metastatic bladder cancer. Based on current literature, 7%-38% of pts with muscle-invasive bladder cancer achieve pathological down-staging (pT0) with neoadjuvant chemotherapy (NC), which correlates with improved disease-free and overall survival. The role of HD-MVAC has not been evaluated in the neoadjuvant setting. In this retrospective study, we present our data in pts who received NC with HD-MVAC or GC followed by radical cystectomy (RC). Methods: From July 2008 to August 2010, 38 (pts) received 4 cycles of NC with either HD-MVAC or GC for at least T2 bladder cancer followed by RC. The endpoints of interest of this study were the complete pathologic response (pT0) or down-staging to < pT2 (pT0, pTis, and pT1) at RC; and median interval to RC from the time of diagnosis of muscle-invasive bladder cancer and start of NC. Results: Median age at the time of diagnosis was 66 years (35-80 years). Fifteen pts received neoadjuvant HD-MVAC, and 23 received neoadjuvant GC. Clinical T stage at the time of diagnosis was T2 in 29 (76%), T3 in 3 (8%), and T4 in 6 (16%) pts. Down-staging to < pT2 was achieved in 8 (53%) of HD-MVAC pts and 10 (43%) of GC pts. pT0 was achieved in 5 (33%) of HD-MVAC pts and 9 (39%) of GC pts. The median interval from time of diagnosis to RC was 129 days (range 84-154) for the HD-MVAC pts, and 145 days (range 108-252) for the GC pts. The median interval from initiation of NC to RC was 85 days (range 53-122) for the HD-MVAC pts and 107 days (range 60-126) for the GC pts. Overall, NC was well tolerated with 80% of HD-MVAC pts and 78% of GC pts completing the planned chemotherapy. To this date, none of the pT0 pts had recurrence. Conclusions: Both neoadjuvant HD-MVAC and GC appear to be well tolerated, with very promising rate of pathological down-staging. Longer follow-up is needed for the survival outcomes of these patients. A shorter interval from diagnosis and initiation of NC to RC might be responsible for our better outcomes comparing to some historical data. No significant financial relationships to disclose.

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Results of the phase I trial of cetuximab with mitomycin c and 5-fluorouracil concurrent with radiotherapy treatment in patients with muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.368 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 368-368

Author(s):

Syed A. Hussain ◽

Carey Hendron ◽

Laura Buckley ◽

Lynne Dickinson ◽

Isabel Syndikus ◽

...

Keyword(s):

Bladder Cancer ◽

Phase I ◽

Mitomycin C ◽

Phase I Trial ◽

Disease Free Survival ◽

Dose Intensity ◽

Complete Response ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive

368 Background: Synchronous chemo-radiotherapy is an alternative to cystectomy in patients with muscle invasive bladder cancer (MIBC). BC2001 trial reported improved local control in patients randomised to synchronous chemo-radiotherapy compared to radiotherapy alone (James, Hussain, Hall et al NEJM 2012). TUXEDO trial reports phase I trial results with additional weekly cetuximab (Cet) in combination with Mitomycin c (MMC), 5-Fluouracil (5-FU) and concurrent radiotherapy (RT). Methods: This two centre phase I trial recruited 7 patients with MIBC in Queen Elizabeth Hospital Birmingham and Clatterbridge Cancer Centre Liverpool to synchronous chemotherapy using Loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2, continuous infusion 5-FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC12mg/m2on day 1 in combination with radical RT treatment 64 Gys in 32 fractions. The primary endpoint was to assess toxicity. Secondary end- points included 3 months pathological complete response, loco-regional disease-free survival and overall survival. Results: Median age of patients was 70 (range: 60-75) years, all were male, 6 had received prior neoadjuvant chemotherapy. Two patients had T2B, 3 T3A and 2 T3B disease, all had G3, TCC disease, 6 patients had neo-adjuvant chemotherapy. All 7 patients completed RT as planned except for 1 who withdrew from trial after 5 weeks of protocol treatment due to relocation. Median dose intensity for Cet and MMC was 97.6% and for 5-FU was 99.4%. Grade 3 toxicity to report was maculopapular rash in 3 patients. Grade 2 toxicities include UTI/ frequency/ nocturia / fatigue /constipation / hypokalemia/epistaxis/palmar-plantar reported in 3/1/1/1/1/1/1/2 cases respectively. Grade 2 maculo-papular rash was reported in 3 cases. All seven patients have achieved complete responses at 3 months cystoscopic assessment. Patients continue on surveillance as per TUXEDO trial protocol. Conclusions: Synchronous chemotherapy with Cet and 5FU/MMC concurrent with radical RT is safe to deliver. Complete response rates are encouraging and a phase II trial with added centres within UK is being launched. Clinical trial information: NOT KNOWN.

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Radiomics-based model for predicting pathological complete response to neoadjuvant chemotherapy in muscle-invasive bladder cancer

Clinical Radiology ◽

10.1016/j.crad.2021.03.001 ◽

2021 ◽

Author(s):

S.J. Choi ◽

K.J. Park ◽

C. Heo ◽

B.W. Park ◽

M. Kim ◽

...

Keyword(s):

Bladder Cancer ◽

Neoadjuvant Chemotherapy ◽

Pathological Complete Response ◽

Complete Response ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Muscle Invasive ◽

Response To Neoadjuvant Chemotherapy

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Neoadjuvant Immunotherapy for Muscle-Invasive Bladder Cancer

Medicina ◽

10.3390/medicina57080769 ◽

2021 ◽

Vol 57 (8) ◽

pp. 769

Author(s):

Arthur Peyrottes ◽

Idir Ouzaid ◽

Gianluigi Califano ◽

Jean-Francois Hermieu ◽

Evanguelos Xylinas

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitor ◽

Response Rate ◽

Checkpoint Inhibitor ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Neoadjuvant Immunotherapy ◽

Muscle Invasive

Background and Objectives: Facing neoadjuvant chemotherapy followed by surgery, neoadjuvant immunotherapy is an innovative concept in localized muscle-invasive bladder cancer. Herein, we performed a review of the available and ongoing evidence supporting immune checkpoint inhibitor (ICI) administration in the early stages of bladder cancer treatment. Materials and Methods: A literature search was performed on Medline and clinical trials databases, using the terms: “bladder cancer” OR “urothelial carcinoma”, AND “neoadjuvant immunotherapy” OR “preoperative immunotherapy”. We restricted our investigations to prospective clinical trials evaluating anti-PD-(L)1 and anti-CTLA-4 monoclonal antibodies. Data on efficacy, toxicity and potential biomarkers of response were retrieved. Results: The search identified 6 ICIs that were tested in the neoadjuvant setting for localized bladder cancer—4 anti-PD-(L)1 inhibitors (Pembrolizumab, Atezolizumab, Nivolumab and Durvalumab) and 2 anti-CTLA-4 inhibitors (Ipilimumab and Tremelimumab). Most of the existing literature was based on single-arm phase 2 clinical trials that included from 23 to 143 patients. The pathological complete response rate (pCR) and pathological response rate (pRR) ranged from 31% to 46% and from 55.9% to 66%, respectively. Survival data were immature at this time. The safety profile was acceptable, with severe treatment-related adverse events ranging from 6% to 41%. Conclusions: The results of early phase trials are encouraging, and more investigations are needed to strengthen the rationale for immune checkpoint inhibitor administration in localized muscle-invasive bladder cancer.

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