ASCO 2019: Randomized Trial of Adjuvant Chemotherapy vs Adjuvant Radiation Therapy for Locally Advanced Bladder Cancer after Radical Cystectomy

Chicago, IL (UroToday.com) Brian C. Baumann, MD, presented a randomized trial of adjuvant chemotherapy vs. adjuvant radiotherapy in locally advanced bladder cancer patients after radical cystectomy.

Neoadjuvant chemotherapy plus radical cystectomy is the standard of care. For chemotherapy-naïve pathological stage T3-T4 or N+ disease, adjuvant chemotherapy is frequently employed. Patients who cannot receive chemotherapy due to underlying comorbidities are at high-risk for recurrence.

There are, however, alternatives to adjuvant chemotherapy. These include immunotherapy and adjuvant radiotherapy. The rationale for adjuvant radiotherapy was next explained by Dr. Baumann. The SWOG 87101 and MRC trials 2,3 had shown that there is a 30% risk of local failure for locally advanced disease (>=pathological stage T3N0). Additionally, there is no reduction in the local failure rate with the addition of chemotherapy. Importantly, local failures are rarely salvageable. The median overall survival after local failure is nine months, with significant associated morbidity. The option of salvage radiotherapy for local failure is often precluded. This is mainly because that after removal of the bladder, more small bowel falls into the pelvis, limiting the radiation dose to 50-54 GY when 60-70 GY is the actual dose required.3,4

Adjuvant Radiotherapy in the appropriate dose has been shown to significantly reduce local failures, compared to chemotherapy alone in a randomized phase 2 trial5 (two-year local control of 96% vs. 69%, p<0.01 for the entire cohort, and 100% vs. 67%, p<0.01 for the urothelial cohort). Reducing local failure rates may improve survival as it may prevent seeding of distant metastasis and could improve survival. The addition of adjuvant radiotherapy improved disease-free survival and overall survival compared to chemotherapy alone, but the difference was not significant, and the study was not powered for those endpoints. In an independent NCDB propensity analysis, adjuvant radiotherapy improved overall survival for locally advanced disease.6 Ideally, adjuvant radiotherapy should be combined with chemotherapy, as radiotherapy can improve the effectiveness of chemotherapy in a synergistic effect.

In a phase 3 study of adjuvant radiotherapy + chemotherapy, compared to radiotherapy alone, the overall survival benefit was in the arm of adjuvant chemotherapy + radiotherapy (two-year overall survival rate of 71% vs. 51%, p<0.05) (Figure 1).6 Chemotherapy and radiotherapy act synergistically to reduce local and distant recurrence. The most recent NCCN guidelines recommend adjuvant radiotherapy along with chemotherapy for pathological stage T3-T4 N0-N+ disease.

Figure 1 – Significant overall survival benefits with adjuvant radiotherapy and chemotherapy compared to radiotherapy alone:
ASCO 2019 Bladder Adjuvant Chemotherapy vs Adjuvant Radiation Therapy 1
Dr. Baumann moved on to ask whether adjuvant radiotherapy can replace chemotherapy altogether. For patients who cannot tolerate chemotherapy, adjuvant radiotherapy has different contraindications and may be a good option that can reduce recurrence. There is also long experience in gynecological oncology using pelvic radiotherapy alone instead of chemotherapy for chemotherapy-intolerant patients. To date, no prospective data have compared adjuvant radiotherapy to adjuvant chemotherapy in bladder cancer patients.

The hypothesis of the presented study was that adjuvant radiotherapy could achieve comparable disease-free survival (DFS) as adjuvant chemotherapy. The presented study was a phase 3 trial conducted at the NCI in Cairo, Egypt, to assess whether the addition of adjuvant chemotherapy improves disease-free survival compared to adjuvant radiotherapy alone in a patient population where adjuvant radiotherapy is the standard of care. A third arm (adjuvant chemotherapy only) was added later, and the results presented in this presentation are specific to the comparison between adjuvant radiotherapy alone and adjuvant chemotherapy alone. The eligibility criteria included bladder cancer patients younger than 70, with an ECOG performance status of 0-2, and adequate liver/renal function. All patients had no evidence of distant metastases or secondary malignancies on imaging. All patients were treated with radical cystectomy and pelvic lymph node dissection with negative margins and more than one of the following factors:

  • - pT3b/T4a
  • - pN+
  • - Grade 3 tumors
The trial design is shown in figure 2, but the actual comparison of the presented results is shown in figure 3. Radiotherapy was given as 3D conformal radiotherapy at a dose of 45 Gy in fractions twice daily, directed at the cystectomy bed plus bilateral pelvic lymph nodes. Chemotherapy was given with gemcitabine + cisplatin, and the cycles were repeated every 28 days. All patients were followed-up every two months in the first two years and then every six months after that. CT imaging was done every six months in the first two years and then yearly. Aside from the standard accepted statistical analyses, exploratory analyses were done as well to estimate whether radiotherapy is non-inferior to chemotherapy for disease-free survival with a non-inferiority margin of 10% at two years.

Figure 2 – Trial design:
ASCO 2019 Bladder Adjuvant Chemotherapy vs Adjuvant Radiation Therapy 2
Figure 3 – Adjuvant radiotherapy vs. chemotherapy comparison:
ASCO 2019 Bladder Adjuvant Chemotherapy vs Adjuvant Radiation Therapy 3
A total of 123 patients were enrolled in the two arms (78 in the radiotherapy arm, and 45 received chemotherapy). The median age was 55 (range 27-70). Overall, 51% had urothelial carcinoma, and 49% had squamous cell cancer. The baseline characteristics are shown in Table 1. The univariable analysis demonstrated no significant predictors of disease-free survival, distant metastasis-free survival, and overall survival. However, for local recurrence-free survival radiotherapy, age, and the number of nodes removed had a statistically significant association. When looking at the multivariable analyses, no predictors were found for disease-free survival. Despite demonstrating no significant differences in distant metastasis-free survival, and overall survival, radiotherapy did seem to improve local control (Figure 4). When specifically examining the subgroup analysis of only patients with urothelial histology, the disease-free survival and overall survival did not significantly differ. Lastly, in the non-inferiority exploratory analysis – the difference in two years of disease-free survival for radiotherapy (54%) vs. chemotherapy (47%) was 7% (favoring radiotherapy).

Table 1 – Baseline characteristics:
ASCO 2019 Bladder Adjuvant Chemotherapy vs Adjuvant Radiation Therapy 4
Figure 4 – Radiotherapy seems to improve local failure:
ASCO2019_radiotherapy.png

Next, Dr. Baumann discussed the toxicity results. 99% of the patients received the prescribed radiotherapy dose with no significant treatment interruptions, and 82% of patients received all cycles of chemotherapy.  Late toxicity was present in 8% and 1% of radiotherapy-treated and chemotherapy-treated patients.

The study had several limitations:
  • It was not designed as a noninferiority trial
  • There were imbalances between the arms concerning gender due to weighted randomization when the 3rd arm was added
  • Heterogeneity of histology
Dr. Baumann concluded that adjuvant radiotherapy is a good option for patients with locally advanced bladder cancer with good performance status where an alternative to chemotherapy is desired. Use of adjuvant radiotherapy is now supported by the NCCN guidelines.

Presented by: Brian C. Baumann, MD, Washington University in St. Louis, St. Louis, MO 

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Grossman HB et al. Neoadjacent chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. 
  2. Christodouleas JP, Baumann BC, et al. Optimizing bladder cancer locoregional failure risk stratification after radical cystectomy using SWOG 8710. Cancer 2014 Apr 15;120(8):1272-80. 
  3. Baumann et al. Int J Rad Biol Phys 2014
  4. Baumann BC et al. The rationale for Post-Operative Radiation in Localized Bladder Cancer. Bladder Cancer. 2017; 3(1):19-30. 
  5. Zaghloul et al. Adjuvant Sandwich Chemotherapy Plus Radiotherapy vs Adjuvant Chemotherapy Alone for Locally Advanced Bladder Cancer After Radical Cystectomy: A Randomized Phase 2 Trial. JAMA Surg. 2018 Jan 17;153(1):e174591`. 
  6. Zaghloul MS et al. 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. GU ASCO 2019. 
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