Adjuvant Chemoradiotherapy May Provide Benefit in Locally Advanced Bladder Cancer

Genitourinary Cancers Symposium

In the United States, the standard of care for locally advanced bladder cancer after radical cystectomy is to “consider” adjuvant chemotherapy and adjuvant radiation. In a 3-arm randomized trial, adjuvant radiation therapy alone or combined with chemotherapy (ie, chemoradiotherapy) did not significantly improve disease-free survival (DFS) compared with adjuvant chemotherapy alone, but the findings hint at benefits for chemoradiotherapy that should be studied further.

The study had 2 main comparisons: adjuvant chemoradiotherapy versus radiation and adjuvant chemoradiotherapy versus chemotherapy alone. Three-year DFS was 68% for adjuvant chemoradiotherapy versus 63% for radiation alone, but this 5% difference was not statistically significant. Three-year DFS in the second comparison was 68% for chemoradiotherapy versus 56% for chemotherapy alone, a numerical trend toward improved survival with chemoradiotherapy.

The rate of local recurrence was significantly reduced with adjuvant chemoradiation versus chemotherapy, and this was the only significant difference between arms reported in this trial. However, improved control of local recurrence did not lead to improved DFS or metastasis-free survival.

The study was conducted in Egypt, where adjuvant radiation therapy is the standard of care for pelvic failure after radical cystectomy. Also, Egyptian patients have more mixed histology with a higher percentage of squamous cell bladder cancer than patients in the United States, explained presenting author Brian Baumann, MD, a radiation oncology resident at University of Pennsylvania, Philadelphia. Lead author Mohamed S. Zaghloul, MD, could not travel from Cairo to make the presentation. Investigators from Penn provided help in analyzing and interpreting the data.

“This is one of the largest trials to be presented, and it provides more evidence that adjuvant chemoradiation may have some benefit in locally advanced bladder cancer. Chemoradiation led to improvement in local control in the second randomization. We think the results are intriguing, and larger studies are needed. Four organizations [worldwide] are currently considering such trials adding radiation to neoadjuvant chemotherapy,” Baumann told listeners.

The study enrolled 198 patients with bladder cancer and at least 1 high-risk feature for local failure (ie, pT3b disease or higher, grade 3 tumors, and positive lymph nodes) treated between 2002 and 2008 at the National Cancer Institute in Cairo. Patients were treated with radical cystectomy and pelvic node dissection with negative margins. Patients were younger than 70 years, had adequate ECOG performance status and organ function. Patients with evidence of distant metastasis or second malignancies were excluded.

Patients were randomized 3 to 6 weeks after radical cystectomy to adjuvant radiation 1.5 Gy twice daily over 3 weeks (45 Gy) or chemotherapy with 2 cycles of gemcitabine/cisplatin followed by adjuvant radiation followed by 2 more cycles of gemcitabine/cisplatin. There were 78 patients in the radiation-alone arm and 75 in the chemoradiation arm. Forty-five patients were later enrolled in the chemotherapy-alone arm (4 cycles of gemcitabine/cisplatin).

Median age was 54 years; 53% had urothelial carcinoma, and 41% had squamous cell carcinoma. Median follow-up was 19 months.

For the initial randomization, the rate of DFS was 68% for the chemoradiation arm versus 63% for the radiation arm—a nonsignificant difference. Local recurrence-free survival at 3 years was 96% with chemoradiation versus 87% for radiation, again a nonsignificant difference.

The rate of distant metastasis-free survival was 73% for chemoradiation versus 72% for radiation, and the overall survival (OS) rate was 64% versus 48%—both nonsignificant differences.

Looking at the second comparison, a trend was seen toward improved DFS with chemoradiation versus chemotherapy alone (68% vs 56%, respectively), and a significant benefit was seen for chemoradiation on local recurrence-free survival (96% vs 69%; P <.0001).

No significant difference was observed between these 2 arms in 3-year metastasis-free survival (64% for chemoradiation vs 51% for chemotherapy alone) or OS. However, the OS analysis numerically favored chemo­radiation over chemotherapy alone: 64% versus 51%.

Baumann cited several limitations of the study. The addition of the third arm led to imbalances in age and tumor size. Further, “the small size of these arms limits the ability to detect clinically meaningful differences between the chemotherapy and chemoradiation arms,” he said, “something that has plagued many adjuvant chemotherapy trials.”

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