Less Aggressive Protocol Suitable for Muscle-invasive Bladder Cancer in Noncystectomy Candidates
Key findings
- NRG Oncology RTOG 0524, a phase 2 trial, assessed chemoradiation with transurethral resection of the bladder tumor in patients with muscle-invasive bladder cancer who were ineligible for radical cystectomy and cisplatin-based chemotherapy
- 45 patients received weekly paclitaxel and daily radiation to the bladder and pelvis for seven weeks; 20 patients received the same plus one weekly dose of trastuzumab for seven weeks
- At one year, most patients had a complete response to therapy (68% of the paclitaxel/radiation group and 72% of the paclitaxel/radiation/trastuzumab group)
- Five-year overall survival rates were 38% and 25%, respectively, and five-year disease-free survival rates were 31% and 15%
- Newer radiation approaches and technologies, and novel immunotherapeutic medications might offer either improved response or better tolerability and convenience. Novel biomarkers may further help with treatment selection in the future
Most patients with muscle-invasive bladder cancer are elderly or have multiple comorbidities. In the U.S., more than 25% of them don't receive any definitive treatment. This is an aggressive cancer for patients who are considered too frail for standard treatments, including radical surgery.
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Douglas M. Dahl, MD, vice-chair in the Department of Urology and chief of the Division of Urologic Oncology, Jason A. Efstathiou, MD, DPhil, vice-chair for Faculty & Academic Affairs and director of the Genitourinary Division in the Department of Radiation Oncology at Massachusetts General Hospital, and colleagues were part of NRG Oncology RTOG 0524, a phase 2 trial designed to assess a novel protocol for patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin.
Their final report in European Urology Oncology includes long-term data on response and survival. Most patients had an initial complete response and were able to keep their bladders, but 65% of patients had recurrent disease or died by year 2.
Methods
65 participants with a mean age of 76 were included in the updated analysis. All underwent maximal transurethral resection of the bladder tumor followed by seven weeks of:
- Weekly paclitaxel, daily radiation to the bladder and pelvis and one weekly dose of trastuzumab (group 1, n=20 whose tumors overexpressed HER2/neu)
- Weekly paclitaxel and daily radiation (group 2, n=45)
Toxicity and early efficacy results were previously reported in the International Journal of Radiation Oncology - Biology - Physics. At the time of this update, 18 deaths (11 cancer-related) had been reported in group 1 and 33 deaths (16 cancer-related) in group 2. The median follow-up time was 2.3 years for all patients and 7.2 years for the 14 surviving patients.
Response
Ten patients died before evaluation of response. For the others the rates of complete response at one year were:
- Group 1—72% (95% CI, 47%–90%)
- Group 2—68% (95% CI, 50%–82%)
Survival
Overall survival was:
- 3-year—50% in group 1, 42% in group 2
- 5-year—25% in group 1, 38% in group 2
- Median—2.8 years in group 1, 2 years in group 2
Disease-free survival was:
- 3-year—25% in group 1, 36% in group 2
- 5-year—15% in group 1, 31% in group 2
- Median—1.1 years in group 1, 0.8 year in group 2
Recurrence and Cystectomy
Details on recurrence were:
- Group 1—Local in 13 patients, pelvic node in 0 and distant in 8 (5 patients had more than one type of recurrence)
- Group 2—18, 2 and 11 (8 patients had more than one type)
Although all trial participants had been deemed unfit for radical surgery, five eventually underwent cystectomy. Among the 34 patients alive at year 2, the bladder-intact survival rate was 91%.
Putting the Results in Context
The trial was not powered to assess efficacy, but disease-free survival seems to be inferior to rates observed when standard radical chemoradiation is administered with concurrent cisplatin or gemcitabine. That's particularly likely because 83% of participants had T2 tumors, whereas other trials have included higher proportions of T3 and T4 disease.
A higher HER2 status has been significantly associated with a higher stage and grade and a poor disease-specific survival, mainly in the muscle-invasive and metastatic setting, which likely explains the lower survival. The results neither support nor refute the value of administering trastuzumab to HER2/neu-positive patients, though the initial response rates are at some level encouraging. The addition of trastuzumab didn't appear to increase local toxicity, but response rates were similar in the two treatment arms.
Since this study was designed, newer radiation approaches for the elderly have been tested in phase 2 studies, including hypofractionation and adaptive radiotherapy with partial bladder radiation, and omission of elective lymph node treatment. Those approaches can't be directly compared with the protocol in this trial, but they combine efficacy with tolerability and convenience (fewer fractions), so they may be preferred by patients.
Immunotherapeutic medication and nonchemotherapy radiation adjuvants may also offer either better response or improved tolerability and convenience. Novel biomarkers may further help with treatment selection in the future.
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