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SAN FRANCISCO -- Adjuvant radiation therapy, alone or with chemotherapy, did not significantly improve disease-free survival (DFS) in locally advanced bladder cancer compared with adjuvant chemotherapy alone, according to results from a three-arm randomized clinical trial.

Combined adjuvant therapy led to a 3-year DFS of 68% compared with 63% for chemotherapy alone. The rate of local recurrence was reduced significantly with adjuvant chemoradiation versus chemotherapy, , of the University of Pennsylvania in Philadelphia, reported here at the Genitourinary Cancers Symposium.

The applicability of the results remains to be seen, as the initial trial design addressed a problem common to areas where adjuvant radiation is standard of care: pelvic failure after radical cystectomy.

"The hypothesis that improving pelvic control increases survival has been lent some credence by a randomized controlled trial of postop radiation versus cystectomy alone, conducted in the 1980s in Egypt," said Baumann, who was presented the data on behalf of lead investigator , of Cairo University in Egypt. "In the study, postoperative radiation not only significantly improved local control but it also significantly improved overall survival (OS). These findings established adjuvant radiation as the standard of care in Egypt, in a population where most patients have squamous-cell disease."

The benefits of adjuvant chemotherapy in bladder cancer are controversial, and accrual to adjuvant chemotherapy trials has been relatively poor. The original purpose of the study Baumann reported was to determine whether sequential adjuvant therapy improves outcomes compared with adjuvant radiation alone.

"To address the question of whether adjuvant radiation, with or without chemo, is any better than chemo alone, a third arm using only adjuvant chemo was added later, with a weighted accrual to speed enrollment," said Baumann.

Eligible patients were those with bladder cancer who were treated with radical cystectomy and pelvic node dissection and negative margins and at least one high-risk feature for local failure, including ≥pT3b disease, grade-3 tumors and pathologically involved positive lymph nodes. Patients had to be younger than 70 years, have an Eastern Cooperative Oncology Group performance status of 0 to 2, have adequate liver and renal function and no evidence of distant metastases or second malignancies on imaging.

The study enrolled 198 patients who underwent cystectomy from 2002 to 2008 at the National Cancer Institute in Cairo.

Patients were randomized 3 to 6 weeks after radical cystectomy to one of the following:

• Adjuvant radiation to 45 Gy given twice daily over 3 weeks (n=78)
• "Sandwich" adjuvant chemoradiation, using two cycles of gemcitabine/cisplatin followed by radiation given as 45 Gy twice daily and then two more cycles of gemcitabine/cisplatin (n=75)
• Chemotherapy alone consisting of four cycles of gemcitabine/cisplatin (n=45). The median patient age was 53 years, 53% had urothelial carcinoma and 41% had squamous cell carcinoma

Radiation was delivered by 3D conformal techniques to the cystectomy bed plus bilateral pelvic lymph nodes. Median follow-up was 19 months.

The 5% absolute difference in DFS in favor of adjuvant chemoradiation versus radiation therapy failed to achieve statistical significance (P=0.29), as did freedom from local disease-free recurrence, 96% at 3 years with chemoradiation compared with 87% for radiation therapy (P=0.13).

There was also no significant difference between the two groups on the endpoints of distant metastases-free survival (73% versus 72%, respectively, P=0.37) or OS (64% vs 48%, respectively, P=0.35).

For the randomized comparison between chemoradiation and chemotherapy alone, patients in the chemotherapy alone group were slightly older at 55 years compared with 52 years in the chemoradiation group (P=0.04) and their mean tumor size was larger (5.8 vs 4.9 cm, P<0.01). There was a trend toward improved 3-year DFS with chemoradiation compared with chemotherapy alone (68% vs 56%, P=0.10) and a significant benefit with chemoradiation on local recurrence-free survival (96% versus 69%, P<0.0001).

There was no significant difference between arms in 3-year metastasis-free survival (73% vs 79%) or OS, but a 13% absolute difference in OS that favored chemoradiation over chemotherapy alone was observed (64% vs 51%, P=0.18).

The radiation and chemoradiation arms were well tolerated. There was a small increased risk of late grade 3 or higher gastrointestinal toxicity in the radiation-containing arms (8% for radiation alone, 7% for chemoradiation, and 2% for chemotherapy alone).

Baumann said that the small size of this trial may limit the ability to detect clinically meaningful differences between the arms, "something that has plagued many adjuvant chemotherapy trials."

Invited discussant , of Fox Chase Cancer Center in Philadelphia, questioned the clinical significance of an improvement in local recurrence without a benefit in metastasis-free survival or overall survival, adding that quality-of-life endpoints should be embedded in future trials of radiation therapy. In addition, given that squamous bladder cancer patients are chemoresistant, she wondered whether this group should be addressed separately in future clinical trials.

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