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.

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.

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.

A randomized clinical trial comparing adjuvant radiation versus chemo-RT versus chemotherapy alone after radical cystectomy for locally advanced bladder cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 356-356 ◽  
Author(s):  
Mohamed S. Zaghloul ◽  
John Paul Christodouleas ◽  
Andrew Smith ◽  
Ahmed Abdalla ◽  
Hany William ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bladder Cancer ◽  
High Risk ◽  
Radical Cystectomy ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Adjuvant Radiation ◽  
Significant Difference ◽  
Advanced Bladder Cancer ◽  
Grade 3

356 Background: There is growing interest in using adjuvant radiation therapy (RT) to reduce local failures (LF) after radical cystectomy (RC) for locally advanced bladder cancer. A previous RCT demonstrated significantly improved LF & OS with adjuvant RT vs. RC alone. An RCT was performed to compare the efficacy of adjuvant RT vs chemo-RT vs chemo alone after RC. The primary endpoint was disease-free survival (DFS). Secondary endpoints were OS, LRFS, DMFS and toxicity. Methods: Patients ≤ 70 yrs with ECOG PS ≤ 2 with locally advanced bladder cancer and ≥ 1 high-risk feature who underwent RC with negative margins at the Egyptian National Cancer Institute from 2002 – 2008 were enrolled. High risk features included stage ≥ pT3b, grade 3, or positive nodes. Patients were randomized following RC to RT (45 Gy in 1.5 Gy/fx given BID with 3D-conformal RT), chemo-RT with 2 cycles of gemcitabine/cisplatin before and after RT, or 4 cycles of chemo alone. The chemo alone arm was added as a 2nd randomization in 2007. Patients were followed regularly with CT scans q 6 months in the first 2 years & then yearly. Results: 198 patients were enrolled. 78 received RT, 75 chemo-RT and 45 received chemo alone. Median age was 54 (range 27 – 70) and the M:F ratio was 4:1. 53% had urothelial carcinoma, 41% had SCC and 6% other. Median follow-up was 19 mo (range 1 – 127 mo). The RT, chemo-RT and chemo alone arms had similar characteristics except for age (median 55, 52 and 55, respectively, p = 0.03) and tumor size (p = 0.02). There was no significant difference in DFS, DMFS or OS, although there was a trend toward improved DFS favoring the RT-containing arms with 3 yr rates of 63%, 68% and 56% in the RT, chemo-RT and chemo arms (p = 0.25). LRFS was significantly improved for the RT arms vs. chemo alone, with 3 yr rates of 87%, 96% and 69% (p < 0.01), regardless of histology. Treatment was reasonably well-tolerated with late grade ≥ 3 GI toxicity of 8%, 7% & 2%, respectively. Conclusions: This is the first RCT comparing adjuvant RT (+/- chemo) vs. adjuvant chemo following cystectomy for bladder cancer. RT was associated with significantly improved local control compared to chemo alone. There was no significant difference in DFS, DMFS, or OS. Clinical trial information: NCT01734798.

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