Stages II and III Bladder Cancer Treatment
Standard Treatment Options for Stages II and III Bladder Cancer
- Radical cystectomy.
- Neoadjuvant combination chemotherapy followed by radical cystectomy.
- External-beam radiation therapy (EBRT) with or without concomitant chemotherapy.
- Segmental cystectomy (in selected patients).
- Transurethral resection (TUR) with fulguration (in selected patients).
The most common treatments for muscle-invasive bladder cancer are radical cystectomy and radiation therapy. There is no strong evidence from randomized controlled trials to determine whether surgery or radiation therapy is more effective. There is strong evidence that both therapies become more effective when combined with chemotherapy. At the present time, the treatments with the highest level of evidence supporting their effectiveness are radical cystectomy preceded by multiagent cisplatin-based chemotherapy and radiation therapy with concomitant chemotherapy.
Radical cystectomy is a standard treatment option for stage II and stage III bladder cancer, and its effectiveness at prolonging survival increases if it is preceded by cisplatin-based multiagent chemotherapy.[1-4] Radical cystectomy is accompanied by pelvic lymph node dissection and includes removal of the bladder, perivesical tissues, prostate, and seminal vesicles in men and removal of the uterus, tubes, ovaries, anterior vaginal wall, and urethra in women.[5-8] Studies of outcomes after radical cystectomy report increased survival in patients who had more, rather than fewer, lymph nodes resected; whether this represents a therapeutic benefit of resecting additional nodes or stage migration is unknown. There are no randomized controlled trials evaluating the therapeutic benefit of lymph node dissection in this setting.
Radical cystectomy is a major operation with a perioperative mortality rate of 2% to 3% when performed at centers of excellence.[6-8] Postoperative complications include ileus. Most men have erectile dysfunction after radical cystectomy; sexual dysfunction after this operation is also common in women.[10-12]
One study of 27 women who underwent radical cystectomy reported diminished ability to have orgasm in 45%, decreased lubrication in 41%, decreased sexual desire in 37%, and pain with vaginal intercourse in 22%. Fewer than one-half were able to have successful vaginal intercourse and most reported decreased satisfaction with their sexual lives after surgery. Studies suggest that radical cystectomy with preservation of sexual function can be performed in some men. In addition, new forms of urinary diversion can obviate the need for an external urinary appliance.[13-16]
In a retrospective analysis from a single institution, elderly patients (≥70 years) in good general health were found to have clinical and functional results after radical cystectomy similar to younger patients.
After radical cystectomy, however, an approximate 30% to 40% risk of recurrence still exists for patients with muscle-invasive disease, even at centers of excellence.[6-8] Five-year overall survival (OS) has generally been reported to be in the range of 50% to 60% but varies by stage. The addition of preoperative radiation therapy to radical cystectomy did not result in any survival advantage when compared with radical cystectomy alone in a prospective randomized trial.
Neoadjuvant combination chemotherapy followed by radical cystectomy
Because bladder cancer commonly recurs with distant metastases, systemic chemotherapy administered before or after cystectomy has been evaluated as a means of improving outcome. Administration of chemotherapy before cystectomy (i.e., neoadjuvant chemotherapy) may be preferable to postoperative treatment because tumor downstaging from chemotherapy may enhance resectability; occult metastatic disease may be treated as early as possible; and chemotherapy may be better tolerated. Currently, the body of evidence supporting preoperative chemotherapy is much stronger than the evidence supporting postoperative chemotherapy.
Evidence (neoadjuvant combination chemotherapy followed by radical cystectomy):
- A controlled trial of preoperative chemotherapy conducted by the Medical Research Council and the European Organization for Research and Treatment of Cancer randomly assigned 976 patients with locally advanced (T3 or T4a) or high-grade muscle-invasive (T2) bladder cancer to undergo either definitive treatment immediately or definitive treatment preceded by three cycles of neoadjuvant cisplatin, vinblastine, and methotrexate.[19,20] In this study, definitive treatment consisted of radical cystectomy (n = 428), radiation therapy (n = 403), or preoperative radiation therapy followed by radical cystectomy (n = 66).
- At a median follow-up of 8.0 years for patients still alive, OS was significantly greater in the arm randomly assigned to receive neoadjuvant chemotherapy (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.72–0.99; P = .037). The survival benefit from neoadjuvant chemotherapy conferred a 6% absolute increase in the likelihood of being alive at 3 years (56% vs. 50%), 5 years (49% vs. 43%), and 10 years (36% vs. 30%).[Level of evidence: 1iiA]
- A randomized study conducted by the Southwest Oncology Group compared three cycles of neoadjuvant cisplatin, methotrexate, vinblastine, and doxorubicin administered before cystectomy with cystectomy alone in 317 patients with stage T2 to stage T4a bladder cancer.
- The study showed that 5-year survival was 57% in the group that received neoadjuvant chemotherapy and 43% in the group treated with cystectomy alone, which is a difference of borderline statistical significance (two-sided P value = .06 by stratified log-rank test).
- No deaths were associated with neoadjuvant chemotherapy, and there was no difference in the rate or severity of postoperative complications in patients who received immediate surgery and in those who received preoperative chemotherapy. Cystectomy was performed as planned for 82% of patients assigned to preoperative chemotherapy and 81% of those assigned to cystectomy alone. This study provided evidence that preoperative chemotherapy does not prevent patients from undergoing cystectomy and does not increase the risk of perioperative complications.
- Thirty-eight percent of patients who received neoadjuvant chemotherapy had a pathologic complete response at the time of surgery, and 85% of those achieving a pathologic complete response were alive at 5 years.
- A meta-analysis of ten randomized trials of neoadjuvant chemotherapy, including updated data for 2,688 individual patients, showed that cisplatin-based combination chemotherapy was associated with a significant 13% relative reduction in the risk of death and resulted in an improvement in 5-year survival from 45% to 50% (P = .016). Neoadjuvant single-agent cisplatin was not associated with any survival benefit in the meta-analysis.
- A subsequent meta-analysis evaluated a nearly identical body of data (11 randomized controlled trials enrolling a total of 2,605 patients) and reached similar conclusions. When the analysis was limited to the eight trials that used multiagent, cisplatin-based chemotherapy, neoadjuvant chemotherapy was associated with a 6.5% absolute benefit in 5-year OS (50% vs. 56.5%; P = .006).
Of note, the vast majority of patients included in these studies received cisplatin, methotrexate, and vinblastine with or without doxorubicin. It is not known whether the doublet regimen of cisplatin plus gemcitabine offers any benefit when administered in the preoperative setting, nor is there any evidence of benefit for carboplatin-based chemotherapy regimens.
On the basis of these findings, preoperative cisplatin-based combination chemotherapy followed by radical cystectomy represents a standard therapeutic option for patients with muscle-invasive bladder cancer who are fit for chemotherapy and for whom the priority is to maximize survival.
External-beam radiation therapy (EBRT) with or without concomitant chemotherapy
Definitive radiation therapy is a standard option that yields a 5-year survival of approximately 30% to 40%. When radiation therapy and chemotherapy are administered concomitantly, the results are better. However, while the addition of chemotherapy to radiation therapy has been shown to reduce local relapse rates, it has not been shown to result in increased survival, decreased mortality, or improved quality of life.
Most protocols for bladder preservation that use combined chemotherapy and radiation therapy have followed a relatively complex algorithm. After the initial stage TUR of the bladder tumor, patients undergo a repeat TUR to maximally resect the tumor. The patient is then treated with synchronous chemoradiation therapy to a dose of roughly 40 Gy followed by a repeat cystoscopy with biopsies to assess for residual cancer. If residual cancer is detected histopathologically, then the chemoradiation therapy is judged to have failed and the patient is advised to undergo a radical cystectomy. If the biopsies at 40 Gy are benign, then chemoradiation therapy is completed to a dose of about 65 Gy.
With definitive radiation therapy, best results are seen in patients with solitary lesions and without carcinoma in situ or hydronephrosis
After radiation therapy, approximately 50% of patients have dysuria and urinary frequency during treatment, which resolves several weeks after treatment, and 15% report acute toxic effects of the bowel.
Randomized trials that directly compare the bladder-preserving chemoradiation therapy approach with radical cystectomy have not been performed; the relative effectiveness of these two treatments is thus unknown.
Evidence (EBRT with or without concomitant chemotherapy):
TUR followed by chemoradiation therapy
- A multicenter phase III trial randomly assigned 360 patients with muscle-invasive bladder cancer to radiation therapy with or without synchronous chemotherapy using fluorouracil and mitomycin C.
- Two-year locoregional disease-free survival was higher in the chemoradiation therapy group (67% vs. 54%; HR, 0.68; 95% CI, 0.48–0.96; P = .03). Five-year OS was 48% in the chemoradiation therapy group and 35% in the radiation therapy group, but the difference was not statistically significant (P = .16).
- Similarly, synchronous chemoradiation therapy using other chemotherapy regimens, such as cisplatin alone or combined with fluorouracil, have reported 5-year OS rates of 50% to 60% and survival with an intact bladder in 40% to 45% of patients, figures that are higher than has generally been reported in studies of radiation therapy alone.
TUR followed by chemoradiation therapy
Radiation therapy and chemotherapy
- A randomized controlled trial randomly assigned 99 patients with T2 to T4b urothelial carcinoma of the bladder to radiation therapy with or without three 14-day cycles of cisplatin (100 mg/m2 on day 1). Patients and their physicians chose whether the radiation therapy was definitive or administered as precystectomy treatment. The pelvic relapse rate was reduced (multivariable regression model HR, 0.50; 90% CI, 0.29–0.86; P = .036), but there was no difference in the occurrence of distant metastases or OS. The reduction in pelvic relapse was similar in patients who received definitive radiation therapy and precystectomy radiation therapy.
Neoadjuvant chemotherapy followed by chemoradiation therapy
- In a phase III study (RTOG-8903), the Radiation Therapy Oncology Group evaluated the potential benefit of adding two cycles of neoadjuvant methotrexate, cisplatin, and vinblastine before concurrent cisplatin and radiation therapy. Neoadjuvant chemotherapy was associated with increased hematologic toxic effects and yielded no improvement in response rate, freedom from distant metastases, or OS compared with chemoradiation therapy alone.
Segmental cystectomy (in selected patients)
Segmental cystectomy is appropriate only in very selected patients. There are no randomized controlled trials comparing segmental cystectomy with radical cystectomy. Only patients with adenocarcinomas of the urachus are routinely treated with segmental cystectomy. These tumors typically are mucinous adenocarcinomas occurring at the dome of the bladder and are treated with an en bloc resection of the bladder dome and urachal remnant, including the umbilicus.[29-32]
TUR with fulguration (in selected patients)
Stage II bladder cancer may be controlled in some patients by TUR, but more aggressive forms of treatment are often dictated by recurrent tumor or by the large size, multiple foci, or undifferentiated grade of the neoplasm.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II bladder cancer and stage III bladder cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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