SWOG-8710: Neoadjuvant Chemotherapy and Cystectomy for Bladder Cancer
Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66. https://www.ncbi.nlm.nih.gov/pubmed/12944571
Clinical Question
In patients with locally advanced bladder cancer, does neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone improve survival?
Bottom Line
Neoadjuvant chemotherapy with M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) improves survival in patients with locally advanced bladder cancer
Major Points
Cystectomy is an aggressive treatment for bladder cancer with considerable impact on quality of life and a high rate of recurrence afterwards. This study sets out to test if neo-adjuvant chemotherapy administered before cystectomy improves survival outcomes in patients with locally advanced disease. In this trial, the median survival with surgery alone was 46 months compared to neoadjuvant therapy plus cystectomy (77 months). In patients treated with neoadjuvant therapy there was significantly more downstaging. In the neoadjuvant chemotherapy group, 38% had no cancer at surgery compared with 15% in cystectomy alone group.
Guidelines
The EAU guidelines on Muscle-invasive and Metastatic Bladder Cancer (2016) state that Neo-adjuvant chemotherapy (NAC) provides better overall survival outcomes for patients (5-8% at 5 years) compared with surgery alone.
The AUA guideline: Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/ASTRO/SUO Guideline (2017) also recommends NAC where patients are eligible for cisplatin, prior to surgery.
Design
- Multicenter, randomized, controlled trial
- N=317
- Experimental - NAC + surgery (n=153)
- Standard - surgery alone (n=154)
- Setting: 126 institutions affiliated with SWOG, the Eastern Cooperative Oncology Group, or Cancer and Leukemia Group B.
- Enrollment: August 1987- July 1998
- Median follow-up: 8.4 years for the standard arm and 8.7 years for the experimental arm
- Analysis: Intention-to-treat
- Primary outcome:
Comparison of survival among patients treated with cystectomy alone with survival among those treated with M-VAC followed by cystectomy. Survival was measured from the time of randomization.
Population
Inclusion Criteria
- Transitional-cell carcinoma of the bladder
- Part of the 126 institutions affiliated with “SWOG”
- TNM stage T2N0M0 to T4aN0M0 bladder cancer who were candidates for radical cystectomy were eligible.
Exclusion Criteria
- Prior pelvic irradiation
- Renal, Hepatic, haematologic failure
- SWOG performance status not 0 or 1.
Baseline Characteristics
- Median age: 63 years
- Sex: 18% female
- Age and tumour stage:
- <65 yr and T2 20%
- <65 yr and T3 or T4a 36%
- >=65 yr and T2 20%
- >=65 yr and T3 or T4a 24%
Interventions
- Randomized to NAC and cystectomy or Cystectomy alone
- NAC was Methotrexate, vinblastine, doxorubicin and cisplatin (MVAC). Three 28-day cycles were administered.
Outcomes
Comparisons are NAC + cystectomy vs. cystectomy alone.
Primary Outcomes
- median survival in months
- 77 (95% CI 55-104 vs. 46 (CI 25-60); p=0.06
Secondary Outcomes
- Treatment effect on tumour stage at the time of surgery
- 38% pT0 vs. 15% (p<0.001)
- Disease specific survival
- 54 bladder cancer deaths vs. 77 bladder cancer deaths (HR 0.60; 95% CI 0.41-0.82; P=0.002)
Subgroup Analysis
Other factors that were studied included the interactions between the treatment group, and the risk stratification factors (Tumour stage – T2 vs. T3 and T4a, and age – under or over 65 years old) and overall survival. No significant difference was found for tumour stage (p = 0.45) or age (p = 0.74) Receiving neoadjuvant therapy, also had no effect on the number of patients proceeding to cystectomy (82% in cystectomy alone group vs. 81% in combination group)
Adverse Events
The adverse events that were described in the study were mostly related to the patients receiving chemotherapy, as this was the differentiating factor between the groups, and introduced a new potential for harm. About 1/3 of patients had significant haematological and gastrointestinal side effects from the M-VAC regimen, most notably neutropaenia (granulocytopaenia), anaemia, thrombocytopaenia, nausea/vomiting, and stomatitis. No patients died as a result of the M-VAC therapy. The other adverse effects mentioned were post-operative complications from the surgery itself. They used a grading system, describing grade 3 events as a ‘moderate adverse events’, grade 4 adverse events as ‘severe adverse events’ and grade 5 events as ‘life-threatening’. One patient from each the cystectomy alone group and combination therapy group died in the post-operative setting. The study described that there was no significant difference between the rates, or the severity of the post-operative complications. The most commonly described complications were Gastrointestinal effects, genitourinary effects, infection and delayed wound healing. The actual nature of the events were not described in the paper.
Criticisms
The recruitment phase lasted 11 years, during which only 317 patients were enrolled. This potentially adds significant variation in disease. Furthermore, there were 126 institutions involved in the recruitment, allowing for significant heterogeneity but only small volumes and experience per site.
A 50% or greater survival difference is a large figure but probably represents the difficulty in recruiting patients for the study.
19 percent of patients in the cystectomy-alone group (30 of 154) did not undergo cystectomy according to the protocol, and no additional information about the alternative treatments given is provided. Although a similar proportion of patients in the chemotherapy group did not undergo surgery, they received at least M-VAC chemotherapy after transurethral resection.
It is not known whether the 77 patients in the cystectomy-alone group who died from bladder cancer received chemotherapy at the time of relapse. If they did, this fact might have substantially modified their survival in view of the results of M-VAC.
Funding
Supported in part by multiple grants from the National Cancer Institute, Department of Health and Human Services.