Adjuvant Chemoradiotherapy in Locally Advanced Bladder Cancer: Hint of Benefit That Needs Confirmation


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We think the results are intriguing, but larger studies are needed. Four organizations worldwide have developed or are developing clinical trials of adjuvant radiation therapy with or without chemotherapy.

Brian Baumann, MD

Adjuvant sequential chemotherapy plus radiation therapy and adjuvant radiation therapy alone significantly improved local tumor control compared with adjuvant chemotherapy alone in locally advanced bladder cancer but the improvement in disease-free survival (3-year disease-free survival of 68% vs 56%, P = .10) was statistically marginal, according to the results of a three-arm randomized trial presented at the 2016 Genitourinary Cancers Symposium.1

The study was conducted in Egypt. The trial was initially designed to compare adjuvant chemotherapy plus radiation vs adjuvant radiation alone, a question that is particularly relevant in Egypt, where adjuvant radiation is the standard of care following radical cystectomy for locally advanced cancers and a large numer of patients have squamous cell disease. A third arm was added later using adjuvant chemotherapy alone to serve as a benchmark to compare the relative effectiveness of adjuvant radiation with or without chemotherapy.

“Postoperative radiation is known to improve local control, and evidence from Egypt suggests that it can improve survival, while the benefit of postoperative chemotherapy is controversial,” said presenting author Brian Baumann, MD, a radiation oncology resident at the University of Pennsylvania, Philadelphia. Mohamed S. ­Zaghloul, MD, of the National Cancer Institute, Cairo, Egypt, is the lead author of this study.

Mohamed S. Zaghloul, MD

Mohamed S. Zaghloul, MD

Study Details

The study enrolled 198 patients with bladder cancer treated between 2002 and 2008 at the National Cancer Institute in Cairo. Investigators at the University of Pennsylvania partnered with the principal investigator to assist with the analysis.

Patients were treated with radical cystectomy and pelvic node dissection with negative margins and had at least one high-risk feature for local failure (ie, pT3b disease or higher, grade 3 tumors, or positive lymph nodes). Patients were younger than age 70, had an adequate Eastern Cooperative Oncology Group performance status, and adequate organ function. Patients with evidence of distant metastasis or second malignancies were excluded.

Patients were randomized 3 to 6 weeks after radical cystectomy to receive either (1) adjuvant radiation alone (45 Gy given twice daily over 3 weeks); (2) sequential chemotherapy plus radiation (two cycles of gemcitabine/cisplatin followed by radiation therapy and then another two cycles of gemcitabine/cisplatin); or (3) chemotherapy alone (four cycles of gemcitabine/cisplatin). There were 78 patients in the radiation-alone arm and 75 patients in the chemoradiotherapy arm. Forty-five patients were enrolled in the chemotherapy-alone arm.

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

Survival Outcomes

For the initial randomization, the 3-year disease-free survival was 68% for the chemoradiotherapy arm vs 63% for the radiation therapy arm—a 5% difference that favored combined therapy but was not statistically significant. Freedom from local disease-free recurrence was 96% at 3 years with chemoradiotherapy vs 87% for radiation alone—a difference that was also not statistically significant.

Postoperative Radiotherapy vs Chemotherapy in Bladder Cancer

  • In a three-arm randomized study of locally advanced bladder cancer, the radiotherapy-containing arms improved local control vs chemotherapy alone.
  • There was a marginally significant trend toward improved disease-free survival but no significant improvement in metastasis-free survival or overall survival with adjuvant sequential chemotherapy plus radiotherapy vs chemotherapy alone.

Distant metastasis-free survival at 3 years was 73% for chemoradiotherapy vs 72% for radiation therapy alone, which was statistically nonsignificant. Three-year overall survival was 64% vs 48%.

Looking at the comparison between chemoradiotherapy and chemotherapy alone, a trend was seen toward improved disease-free survival with the combination therapy vs chemotherapy alone (68% vs 56%, respectively, P = .10). In addition, a significant benefit was seen for chemoradiotherapy vs chemotherapy alone for local recurrence-free survival (96% vs 69%, P < .0001).

No significant difference was observed between these two arms in 3-year metastasis-free survival (73% vs 79%, respectively) or overall survival. However, the difference in 3-year overall survival favored chemoradiotherapy over chemotherapy alone (64% vs 51%, P = .18).

Study Limitations

Dr. Baumann cited several limitations of the study. The weighted accrual of the third arm caused imbalances between the arms with respect to age and tumor size, since patients in the chemotherapy alone arm were slightly older and had slightly larger tumors. Furthermore, “the small size of the study limits the ability to detect clinically meaningful differences between the chemotherapy and chemotherapy plus radiation arms,” he said, which is “something that has plagued many adjuvant chemotherapy trials.”

Also, it is not clear to what extent these results are applicable to North America because of the heterogeneity of bladder cancer in the Middle East.

“We think the results are intriguing, but larger studies are needed. Four organizations worldwide have developed or are developing clinical trials of adjuvant radiation therapy with or without chemotherapy, including the currently accruing NRG trial, NRG-GU001,” said Dr. Baumann. ■

Disclosure: Drs. Baumann and Zaghloul reported no potential conflicts of interest.

2016 Genitourinary Cancers Symposium: Hans J. Hammers, MD, PhD, gives keynote talk​ during Renal Cancer Keynote Lectures: Immune Checkpoint Blockers—Science and Clinic​. Photo by © ASCO/Todd Buchanan 2016.

Reference

1. Zaghloul MS, Christodouleas JP, Smith A, et al: A randomized clinical trial comparing adjuvant radiation versus chemo-RT versus chemotherapy alone after radical cystectomy for locally advanced bladder cancer. 2016 Genitourinary Cancers Symposium. Abstract 356. Presented January 8, 2016.


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