Adjuvant Cisplatin Plus Methotrexate Versus Methotrexate, Vinblastine, Epirubicin, and Cisplatin in Locally Advanced Bladder Cancer: Results of a Randomized, Multicenter, Phase III Trial (AUO-AB 05/95)

2005 ◽  
Vol 23 (22) ◽  
pp. 4963-4974 ◽  
Author(s):  
Jan Lehmann ◽  
Margitta Retz ◽  
Christina Wiemers ◽  
Joachim Beck ◽  
Joachim Thüroff ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Who Grade ◽  
Free Survival ◽  
Advanced Bladder Cancer ◽  
Grade 3

Purpose Radical cystectomy as standard treatment of muscle-invasive urothelial carcinoma of the urinary bladder cures less than 50% of patients with locally advanced bladder cancer. We compared two adjuvant combination chemotherapies in patients with stage pT3a-4a and/or pathologic node-positive transitional-cell carcinoma of the bladder after radical cystectomy. Patients and Methods A total of 327 patients were randomly assigned to either adjuvant systemic chemotherapy with three cycles of cisplatin 70 mg/qm2 on day 1 and methotrexate 40 mg/qm2 on days 8 and 15 of a 21-day cycle (CM) or three cycles of methotrexate 30 mg/qm2 on days 1, 15, and 22, vinblastine 3 mg/qm2 on days 2, 15, and 22, epirubicin 45 mg/qm2 on day 2, and cisplatin 70 mg/qm2 on day 2 of a 28-day cycle (M-VEC). Results The hazard ratio for progression-free survival as the primary end point was 1.13 (90% CI, 0.86 to 1.48) for 163 CM patients compared with 164 M-VEC patients whose right-hand limit remained below the upper bound compatible with the noninferiority hypothesis (α = .0403). The 5-year progression-free, tumor-specific, and overall survival rates (point estimates ± SE) for CM versus M-VEC were 46.3% ± 4.6% v 48.8% ± 4.5%, 52.0% ± 4.6% v 52.3% ± 4.8%, and 46.1% ± 4.3% v 45.1% ± 4.6%, respectively. WHO grade 3 and 4 leukopenia occurred in 7.0% of patients treated with CM and 22.2% of patients treated with M-VEC (P < .0001). Conclusion CM cannot be considered inferior to M-VEC with regard to progression-free survival of patients with locally advanced bladder cancer after radical cystectomy. Moreover, patients receiving adjuvant CM combination therapy experienced significantly less grade 3 and 4 leukopenia than patients treated with M-VEC.

Prospective trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 515-515
Author(s):  
Mohamed S. Zaghloul ◽  
John Paul Christodouleas ◽  
Tarek Zaghloul ◽  
Andrew Smith ◽  
Ahmed Abdalla ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Locally Advanced ◽  
Prospective Trial ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Adjuvant Radiation ◽  
Free Survival ◽  
Advanced Bladder Cancer ◽  
Grade 3

515 Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemo or decline it. Adjuvant radiotherapy (RT) is an alternative (or complementary) adjuvant therapy, but is rarely performed, with most of these patients being observed. In a prospective trial, we compared RT vs adjuvant chemo & hypothesized that RT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial at the National Cancer Institute (Cairo) compared adjuvant RT (standard of care in Egypt) vs. chemo+RT after RC for LABC. A 3rd arm, adjuvant chemo, was added later (gemcitabine/cisplatin x 4). Herein, we report results of RT vs adjuvant chemo. Patients ≤70 y/o with ≥1 of the following (pT3b/T4a, grade 3 or pN+) with negative margins after RC were eligible. RT was delivered with 3-D conformal RT to the pelvis (45 Gy in 1.5 Gy BID). Routine follow-up & pelvic CT q 6 months were performed. Post hoc non-inferiority exploratory analysis was performed. Results: 123 were enrolled (78 RT/45 chemo). 51% had urothelial carcinoma; 49% had squamous cell carcinoma. The arms were well-balanced except for gender (p=0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for RT vs chemo were 54% vs 47% for DFS [HR 0.65(95%CI 0.35-1.19, p=0.16]; 92% vs 69% for local-regional recurrence-free survival [HR 0.28(95%CI 0.10-0.82), p=0.02]; 75% vs 79% for distant metastasis-free survival [HR 2.39(95%CI 0.94-6.09), p=0.07]; 61% vs 60% for overall survival [HR 0.94(95%CI 0.52-1.69), p=0.83]. In the urothelial cohort, there were no differences in DFS or OS. Late grade ≥3 GI toxicity was observed in 6 RT patients (8%) & 1 chemo patient (2%). Based on our data, there is a >90% probability that the true difference in 2-year DFS is <10%, the prespecified non-inferiority margin. Conclusions: This prospective study demonstrates that adjuvant RT has superior local control vs adjuvant chemo with no statistically significant differences in DFS or OS. Results suggest that RT can be an option for patients with LABC after RC where an alternative to chemo is desired by the patient or physician. Clinical trial information: NCT01734798.

Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4507-4507 ◽  
Author(s):  
Mohamed S. Zaghloul ◽  
John Paul Christodouleas ◽  
Tarek Zaghloul ◽  
Andrew Smith ◽  
Ahmed Abdalla ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bladder Cancer ◽  
Adjuvant Chemotherapy ◽  
Radical Cystectomy ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Adjuvant Radiation ◽  
Advanced Bladder Cancer ◽  
Grade 3

4507 Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemotherapy or decline it, even though such treatment may be warranted. There is no clear alternative adjuvant therapy for these patients, who are usually observed. In this study, we compare post-op radiotherapy (PORT) vs. adjuvant chemotherapy in a randomized clinical trial. We hypothesized that PORT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. In 2007, a third arm comparing adjuvant chemo was added. Herein, we report the results of PORT vs. adjuvant chemo. Patients ≤70 y/o with ≥1 of the following factors (≥pT3b/T4a, grade 3, or positive nodes) with negative margins after RC + pelvic node dissection were eligible. Routine follow-up & pelvic CT q6 months were performed. PORT included 3D conformal pelvic RT (45Gy/1.5Gy BID). Chemo included gemcitabine/cisplatin x 4. Post-hoc non-inferiority exploratory analysis was performed. Results: The PORT arm accrued 78; the chemo arm accrued 45. 51% had urothelial carcinoma; 49% had squamous cell carcinoma/other. The two arms were well-balanced except for gender (p = 0.06). Two-year outcomes & overall adjusted hazard ratios (HR) for PORT vs. chemo alone were 54% vs. 47% (HR 0.65(95%CI 0.35-1.19, p = 0.16) for DFS; 92% vs. 69% (HR 0.28(95%CI 0.10-0.82), p = 0.02 for LRFS; 75% vs. 79% (HR 2.39(95%CI 0.94-6.09), p = 0.07) for DMFS; 61% vs. 60% (HR 0.94(95%CI 0.52-1.69), p = 0.83) for OS. Late grade ≥3 GI toxicity was observed in 6 PORT patients (8%) & 1 chemo patient (2%). Based on our data, there is a greater than 90% probability that the true difference in 2 yr DFS is less than 10%, the pre-specified non-inferiority margin. Conclusions: This randomized study demonstrates superior local control with PORT vs. adjuvant chemo with no significant differences in DFS, DMFS or OS. Results suggest that PORT could be an option for patients with LABC after RC who are medically unfit for adjuvant chemo or who decline it. Clinical trial information: NCT01734798.

Randomized phase III trial of adjuvant sequential chemotherapy plus radiotherapy versus adjuvant radiotherapy alone for locally advanced bladder cancer after radical cystectomy: Urothelial carcinoma subgroup analysis.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 351-351
Author(s):  
Mohamed S. Zaghloul ◽  
John Paul Christodouleas ◽  
Wei-Ting Hwang ◽  
Andrew Smith ◽  
Ahmed Abdalla ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Radical Cystectomy ◽  
Subgroup Analysis ◽  
Locally Advanced ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Advanced Bladder Cancer ◽  
Gi Toxicity ◽  
Grade 3

351 Background: The role of post-operative chemotherapy after radical cystectomy (RC) is not well-defined. While some retrospective studies have shown a benefit, trials have been under-powered. In a phase III Egyptian trial, we evaluated the benefit of adjuvant chemo in locally advanced bladder cancer (LABC) patients treated with post-operative radiotherapy (PORT). In this study, we report a post-hoc subgroup analysis of patients with urothelial histology. We hypothesized that the addition of adjuvant chemo would improve disease-free survival (DFS) compared to PORT alone for LABC. Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC & accrued from 2002–2008 at the NCI in Cairo. Bladder cancer pts ≤70 with at least one of the following factors (≥pT3b, grade 3, positive nodes) with negative margins after RC plus pelvic node dissection were eligible. RT was delivered using 3-D conformal RT to the pelvis to 45Gy in 1.5Gy BID. Chemo+PORT included 2 cycles of gemcitabine/cisplatin before & after RT. The primary endpoint was DFS. Secondary endpoints included overall survival (OS) & late GI toxicity. Results: 153 pts were enrolled. 53% had urothelial carcinoma (41 chemo+PORT & 40 PORT). In the urothelial cohort, the arms were well-balanced. Median age was 55. Median follow-up was 21 months for chemo+PORT (range 4-127) & 15 months for PORT (range 5-70). There were 2 local failures for PORT & none for chemo+PORT. Two-year DFS for chemo+PORT vs. PORT was 62% (95% CI 53-71%) & 48% (95% CI 39-58%), log-rank p=0.031. Two-year OS was 71% (95% CI 63-80%) & 51% (95% CI 40-61%), log-rank p=0.048. On multivariable analysis, chemo+PORT was a significant predictor of improved DFS (HR 0.42 95% CI 0.21-0.85, p=0.016) and OS (HR 0.45, 95% CI 0.21-0.96, p=0.039). In the entire cohort, late grade ≥3 GI toxicity was observed in 5 chemo+PORT patients (7%) & 6 PORT patients (8%). Conclusions: The addition of adjuvant chemo to PORT improved DFS & OS for LABC after RC with acceptable late GI toxicity. The results suggest a role for adjuvant therapies to address both local & distant disease. Clinical trial information: 01734798.

Results of a phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim (PEG) in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab (B) for colorectal cancer (CRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3575-3575
Author(s):  
Tamas Pinter ◽  
Esteban Abella ◽  
Alvydas Cesas ◽  
Adina Croitoru ◽  
Jochen Decaestecker ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Double Blind ◽  
Free Survival ◽  
Clinically Significant ◽  
Grade 3

3575 Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. his trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally-advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ≥ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N = 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p = 0.014. A similar incidence of other ≥ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. [Table: see text]

Results of a phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim (PEG) in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab (B) for colorectal cancer (CRC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. LBA445-LBA445 ◽  
Author(s):  
Tamas Pinter ◽  
Steve Abella ◽  
Alvydas Cesas ◽  
Adina Croitoru ◽  
Jochen Decaestecker ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Double Blind ◽  
Free Survival ◽  
Clinically Significant ◽  
Grade 3

LBA445 Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. This trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ≥ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N = 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p = 0.014. A similar incidence of other ≥ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See Table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. [Table: see text]

scholarly journals Tolerability and Efficacy of Neoadjuvant Chemotherapy with a Tri-Weekly Interval Methotrexate, Doxorubicin, Vinblastine, and Cisplatin Regimen for Patients with Locally Advanced Bladder Cancer

2018 ◽  
Vol 11 (2) ◽  
pp. 450-460 ◽  
Author(s):  
Satoko Arai ◽  
Tomohiko Hara ◽  
Yoshiyuki Matsui ◽  
Keiichi Koido ◽  
Hironobu Hashimoto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Survival Rates ◽  
Dose Intensity ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Advanced Bladder Cancer ◽  
Grade 3 ◽  
Muscle Invasive

Objective: Compared with standard treatment, a modified tri-weekly MVAC (methotrexate, doxorubicin, vinblastine, and cisplatin) treatment regimen with a high cisplatin dose intensity shows good efficacy and lower toxicity. Thus, we retrospectively investigated the tolerability and efficacy of a modified tri-weekly MVAC neoadjuvant regimen. Methods: We analyzed 25 patients with locally advanced bladder cancer medicated by a modified tri-weekly MVAC neoadjuvant regimen that omits treatment on days 15 and 22. The efficacy and tolerability were assessed retrospectively. Results: The numbers of patients in clinical stages 2, 3, and 4 were 13 (52.0%), 1 (4.0%), and 11 (44.0%), respectively. Surgery could be performed on all patients. Five patients (20.0%) had no cancer remaining in their surgical specimens. Remaining non-muscle-invasive cancer without metastasis was observed in 7 patients (28.0%), and the total downstaging rate was 44.0%. The 5-year overall and relapse-free survival rates were 79.0 and 75.0%, respectively. The overall relative dose intensity was 0.90. Serious hematologic toxicities rated grade 3 or greater were leukopenia in 6 patients (24.0%) and anemia in 1 patient (4.0%). Conclusions: Sufficient efficacy and tolerability of a modified tri-weekly MVAC neoadjuvant regimen were suggested. Thus, tri-weekly modified MVAC may be an option for neoadjuvant chemotherapy of advanced bladder cancer.

scholarly journals Neoadjuvant chemotherapy versus cystectomy in management of stages II, and III urinary bladder cancer

2014 ◽  
Vol 86 (4) ◽  
pp. 278 ◽  
Author(s):  
Mohammed A. Osman ◽  
Ayman M. Gabr ◽  
Mohammad S. Elkady
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Urinary Bladder ◽  
Radical Cystectomy ◽  
Progression Free Survival ◽  
Urinary Bladder Cancer ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Free Survival ◽  
And Performance

Purpose: This phase III trial was de - signed to compare the survival benefit, surgical respectability, and toxicities among patients treated by neoadjuvant chemotherapy followed by radical cystectomy (arm A), with those treated by radical cystectomy (arm B) in the management of stage II, III urinary bladder cancer. Patients and Methods: For inclusion, patients should have pathologically proven urothelial carcinoma in urinary bladder, clinical stages from T2N0M0 to T4aN0M0, patient age less than 65 years, and performance state ≤ 2. Additionally, patients should have adequate hematological, renal, and liver functions. Arm A patients underwent 3 cycles of neoadjuvant cisplatin and gemcitabine followed by radical cystectomy, while arm B patients underwent radical cystectomy directly. Results: Thirty patients had been enrolled in each arm between September 2009 and April 2014 in 3 educational institutes in Egypt. The 3 year OS (overall survival) for arm A, and B were 60% and 50% respectively. The median OS for arm A was 36+ months and that for arm B was 32.5 months. The 3 year progression-free survival (PFS) for arm A, and B were 57% and 43% respectively. The median PFS for arm A was 36+ months and for arm B was 28 months. A subgroup analysis was performed to correlate between 3 year OS and predetermined prognostic factors including age, tumor size, pathological stage, and the response to neoadjuvant chemotherapy. The later was performed only in arm A. Both treatment arms were tolerated well with mild toxicities profiles. Conclusion: Neoadjuvant chemotherapy achieved better survival, surgical respectability, with nearly equivalent toxicities when compared with radical cystectomy.

scholarly journals Factors affectıng recurrence after trımodal treatment ın ınvasıve bladder cancer

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Mehmet Solakhan ◽  
Necla Benlier ◽  
Zeliha Yıldırım ◽  
Ali Ihsan Seran ◽  
Vildan Kaya ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Locally Advanced ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Tumor Location ◽  
Free Survival ◽  
Factors Affecting ◽  
Lymphocyte Ratio ◽  
Trimodal Therapy

Abstract Background In this study, we aimed to determine which patients will benefit most from TMT treatment, and to evaluate the factors affecting relapse, survival and response to treatment separately. Methods For the study, patients who presented to our hospital’s outpatient clinic between 2010 and 2020 and were diagnosed with locally advanced (T2-G3) invasive urothelial bladder cancer and treated with gemcitabine concomitantly with radiotherapy following complete TUR were identified. A total of 112 patients with transitional cell bladder cancer invading the muscle were enrolled in the study including 88 (78.6%) males and 24 (21.4%) females. Results Tumor location was significantly associated with tumor recurrence (p = 0.003). Recurrence at follow-up was significantly associated with the number of tumor foci (p = 0.008). Median duration of follow-up and median progression-free survival were 41.50 months and 65 ± 4.21 (95% CI, 56.74-73.25) months, respectively. Progression-free survival was not statistically significantly associated with neutrophil/lymphocyte ratio (NLR), platelet/ lymphocyte ratio (PLR) or BMI (p = 0.32, p = 0.47, p = 0.39, respectively), but muscle invasion during follow-up was significantly associated with progression-free survival (p = 0.009). Conclusions Tumor location, the number of tumor foci, history of multiple transurethral resection surgeries and a NLR ≥ 2.56 were significantly associated with recurrence following Trimodal therapy (TMT). A lower rate of recurrence was observed among patients undergoing early TMT after initial diagnosis. None of the patients treated with trimodal therapy experienced severe adverse effects. Therefore, trimodal therapy is a safe, effective and tolerable therapeutic option with a low rate of recurrence in selected eligible patients.

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