In the European Organisation for Research and Treatment of Cancer (EORTC) 30994 trial, a phase III intergroup study reported in The Lancet Oncology,¹ Cora N. Sternberg, MD, FACP, Chief of Medical Oncology at San Camillo and Forlanini Hospitals, Rome, and colleagues found no overall survival difference between immediate and delayed adjuvant chemotherapy after radical cystectomy in patients with muscle-invasive urothelial carcinoma of the bladder.¹ Immediate treatment was associated with improved median and 5-year progression-free survival.

The trial was closed due to slow recruitment after enrollment of 284 of a planned 660 patients. Nevertheless, this is the largest randomized trial in this setting to date.

Study Details

In this open-label trial, 284 patients from 12 countries in Europe (n = 272) or Canada with pT3–pT4 or N+ M0 disease after radical cystectomy and bilateral lymphadenectomy and no evidence of microscopic residual disease were randomly assigned within 90 days of cystectomy, between April 2002 and August 2008, to receive immediate chemotherapy (n = 141) or chemotherapy delayed until relapse (n = 143).

Immediate chemotherapy consisted of four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin (high-dose MVAC), or MVAC; deferred chemotherapy consisted of six cycles of treatment. The primary endpoint was overall survival in the intention-to-treat population.

Overall, patients had a median age of 61 years, 80% were male, 61% had pT3 and 17% had pT4 disease, and 70% had pN+ disease. In the immediate- and deferred-chemotherapy groups, 18% and 19% were pN− based on < 15 dissected nodes, 12% in both groups were pN− based on ≥ 15 nodes, 43% and 46% were pN+ based on < 15 nodes, and 28% and 23% were pN+ based on ≥ 15 nodes. The median time from cystectomy to randomization was 63 days.

In total, 195 patients received chemotherapy, which consisted of gemcitabine plus cisplatin in 165 (85%). In the immediate-chemotherapy group, treatment was started in 128 (91%) of 141 patients, with 28 receiving fewer than four cycles. Among patients in the deferred-treatment group, 3 (2%) requested and received immediate chemotherapy, 64 (45%) started deferred chemotherapy at the time of progression, and 76 (53%) never started deferred treatment; of the latter, 53 (70%) did not exhibit progression. Among the 64 patients who received deferred treatment, 44% received fewer than six cycles.

Survival Data

Data cutoff occurred in August 2013. After median follow-up of 7.0 years (interquartile range = 5.2–8.7 years), 66 patients (47%) in the immediate-treatment group and 82 (57%) in the deferred-treatment group had died, with death due to bladder cancer occurring in 37% and 45%. Five-year overall survival was 53.6% (95% confidence interval [CI] = 44.5%–61.8%) vs 47.7% (39.1%–55.8%) and median overall survival was 6.74 years (95% CI = 3.85 years–not reached) vs 4.60 years (2.15–6.25 years), yielding an adjusted hazard ratio (HR) of 0.78 (95% CI = 0.56–1.08, P = .13).

Five-year mortality due to bladder cancer was 38.6% vs 43.5% (competing risk–adjusted HR = 0.80, P = .22). No significant difference in mortality due to other or unknown causes was observed (competing risk HR = 0.84, P = .61).

As of the data cutoff, progression or death had occurred in 45% of the immediate-treatment group vs 62% of the deferred-treatment group, including distant spread at first diagnosis of progression in 28% vs 37%. Five-year progression-free survival was 47.6% vs 31.8% and median progression-free survival was 3.11 years vs 0.99 years (HR = 0.54, P < .0001).

Homogeneity of Effects in Subgroups

Post hoc exploratory analyses to assess the effect of treatment according to age, sex, pT category, pN category, pTN category, and time from cystectomy to randomization showed a significant interaction for pN category (pN− vs pN+, P = .026 for interaction) for overall survival and no significant interactions for progression-free survival. A significant interaction for overall survival by extent of lymph node sampling was also observed (P = .028 for interaction), but interpretation of the finding is unclear due to the small numbers of patients in the subcategories.

Five-year overall survival was 79.5% vs 59.0% (HR = 0.37, P = .012) in patients without lymph node involvement at baseline and 42.7% vs 42.9% (HR = 0.94, P = .72) in those with involvement at baseline. A second primary cancer or myelodysplastic syndrome occurred in 1% vs 7% in these subgroups, respectively.

Toxicity

Grade 3 or 4 myelosuppression occurred in 26% of 128 patients who received treatment in the immediate-chemotherapy group and 35% of 68 who received treatment in the deferred-chemotherapy group, including neutropenia in 38% and 53%, thrombocytopenia in 28% and 38%, and anemia in 8% and 16%. A cycle of treatment was postponed for a maximum of 2 weeks due to adverse events in 59% and 70%, dose reduction occurred in 51% and 78%, and treatment was discontinued due to adverse events in 11% and 10%. Death due to toxicity occurred in two patients: one in the immediate-chemotherapy group (neutropenic sepsis) and one in the deferred-chemotherapy group (unknown cause 2 weeks after completing treatment).

The investigators concluded: “Our data did not show a significant improvement in overall survival with immediate vs deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients.” ■

Disclosure: The study was funded by Eli Lilly and the Canadian Cancer Society Research Institute. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Sternberg CN, Skoneczna I, Kerst JM, 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. Lancet Oncol 16:76-86, 2015.

See commentary by Maha Hussain, MD, FACP, FASCO.