Case study 96.1

A 68-year-old man with muscle invasive bladder cancer undergoes a radical cystectomy for muscle invasive bladder cancer.

1. Which of the following is true regarding a lymph node dissection?

The extent of pelvic lymph node dissection affects survival outcomes post cystectomy
Pelvic lymph node dissection is only necessary for patients with nodal involvement
Pelvic lymph node dissection is unnecessary in patients who have received neoadjuvant chemotherapy
Lymph node dissection only benefits patients with negative surgical margins

A radical cystectomy is an extensive operation. In men, the urinary bladder is removed along with the prostate and seminal vesicles. In women, en bloc resection of the uterus, cervix, ovaries, and anterior vagina is performed. A lymph node dissection is also undertaken in all patients, and a urinary diversion, typically an ileal conduit or orthotopic neobladder, is created. Multiple groups have published outcomes on series of patients who have undergone cystectomy, and primary T stage and lymph node involvement appear to be predictive of outcomes. The 5-year recurrence-free survival rates range from as high as 70% to 80% for patients with organ-confined disease and absence of nodal involvement to as low as 30% to 35% for those with positive nodes. Patients with a clear extension through the bladder wall (pT3b) and negative nodes have a 5-year recurrence-free rate on the order of 50% to 60%. The median time to recurrence in one series was 12 months.

The quality of the radical cystectomy performed affects patients’ outcomes, particularly in regard to lymph node dissection and margin status. Much debate has centered over the extent of surgery required to optimize outcomes for bladder cancer patients. However, several reports suggest that an extended lymph node dissection improves survival relative to a limited lymph node dissection, regardless of nodal status. Positive surgical margins confer a significant independent risk of reduced recurrence-free and overall survival, but even these patients benefit from a quality pelvic lymph node dissection. Analyses vary in regard to the ideal number of nodes that should be removed, ranging from as few as 3 nodes to at least 10 nodes. One group has concluded that rather than a minimum number of nodes, the probability of survival continues to rise as the number of lymph nodes removed increases. In the Southwest Oncology Group’s SWOG 8710, a randomized trial of neoadjuvant chemotherapy followed by cystectomy versus surgery alone, obtaining negative margins and removing 10 or more lymph nodes were associated with a longer postcystectomy survival regardless of the assigned treatment arm.

Case study 96.2

A 77-year-old woman with multiple medical problems presents to you for a second opinion regarding management of her high-grade, muscle-invasive urothelial carcinoma of the bladder. On a CT scan, asymmetric thickening of the bladder wall is noted, but no lympadenopathy, hydronephrosis, or evidence of visceral metastases is identified. Her urologist is recommending surgery, but she is refusing. While she states that she is appalled at the idea of not having a bladder, she desires active treatment for her cancer. You worry about her ability to tolerate surgery given her multiple comorbidities, including coronary artery disease and diabetes mellitus. She asks if she has options other than surgery.

1. How do you respond?

Reassuring her and sending her back to her urologist for cystectomy
Offering her MVAC in place of surgery
Considering a bladder-sparing or trimodality treatment strategy
Referring for radiation alone

A number of patients are not appropriate for radical cystectomy. Often, this is because of comorbidities or performance status, but occasionally patients refuse surgery. Definitive radiation has been utilized instead of surgery, but as a single modality it may be inferior to surgery as up to 70% of patients may experience a local recurrence and 5-year survival rates are generally suboptimal. The addition of chemotherapy has been shown to improve local control but not overall survival.

Bladder-sparing or trimodality approaches involve a maximum TURBT followed by bladder irradiation concurrent with radiosensitizing chemotherapy. Ideal patients have undergone a complete TURBT as this is a prognostic factor for long-term survival with this approach. Other clinical patient factors to consider include the ability to tolerate platinum-based chemotherapy, urothelial carcinoma histology, and early-stage as opposed to bulky disease. Periodic imaging studies and cystoscopies are performed to monitor for recurrence, and if disease is noted, patients undergo salvage radical cystectomy. To date, there has not been a randomized trial to compare bladder preservation versus neoadjuvant chemotherapy followed by cystectomy.

A phase III trial was recently reported in which patients who had undergone a complete TURBT were randomized to radiation alone or to radiation in combination with mitomycin-C and fluorouracil. Two-year loco-regional disease-free survival was improved from 54% with radiation alone to 67% with combination therapy. However, the difference in overall survival at 5 years, 35% with radiation alone versus 67% with combination therapy, did not reach statistical significance. While the 11% rate of cystectomy at 2 years in the combination arm was less than a rate of 17% with radiation alone, this difference also did not reach statistical significance. With the exception of gastrointestinal toxicity, which increased from 3% with radiation alone to 10% with the addition of chemotherapy, toxicity was similar in the two arms of the study.

For the patient in this question, a trimodality approach is likely the best option. Radiation alone likely has inferior results, and the addition of the mitomycin and 5-fluorouracil regimen does not appear to increase toxicity for most patients. Systemic chemotherapy alone is not a substitute for local therapy, and in this elderly woman with multiple comorbidities, her ability to tolerate platinum-based regimens is questionable, although in smaller phase II studies the results are best when cisplatin is included with radiation. In our practice, we do utilize a trimodalty approach, but only for select patients who are poor cystectomy candidates due to either advanced age or comorbidities or for rare patients who refuse cystectomy. Otherwise, neoadjuvant chemotherapy followed by cystectomy is our preferred treatment strategy.

Case study 96.3

1. A 72-year-old man with muscle-invasive bladder cancer presents to you for a second opinion. Aside from hypertension, he has no significant past medical history or comorbidities. He states that although he is reluctant to undergo cystectomy as recommended to him by his urologist, he wishes to be aggressive with his treatment plan, taking advantage of any possibility to improve his outcome. You realize that his urologist has not discussed neoadjuvant chemotherapy, and you discuss it with the patient, stating that it has which of the following advantages?

An improvement in overall survival
An increase in pathologic complete response rate
No increase in surgical complication rates compared with surgery alone
All of the above

Long-term survival following surgery has been evaluated in multiple surgical series, and the 5-year survival for patients with pathologically organ-confined bladder cancer (pT2) is 68%, while those with extravesicular extension or lymph node involvement have a 25 to 30% 5-year survival rate. As a means to improve outcomes, perioperative chemotherapy has been evaluated in a number of studies. The goal of neoadjuvant chemotherapy is to eradicate micrometastatic disease and improve survival. This approach has several advantages. These include potential downstaging of disease, being able to monitor an intact bladder lesion for response, and avoiding potential postoperative issues or complications that may complicate the delivery of chemotherapy. However, opponents argue that patients may progress such that they become inoperable, losing an opportunity for cure. Further, given the inaccuracies of clinical staging, some patients may be exposed to chemotherapy unnecessarily.

The benefit of neodjuvant chemotherapy is supported by clinical trial data. An Intergroup-sponsored study, INT-0080, randomized patients with clinical T2 to T4a disease to either neoadjuvant MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) followed by radical cystectomy or to surgery alone. Neoadjuvant chemotherapy increased the pathologic complete response rate significantly from 15% with surgery alone to 38% with neoadjuvant MVAC. Further, 85% of patients with a pathologic complete response were alive at 5 years. Median overall survival also was greater with neoadjuvant chemotherapy at 77 months versus 46 months with cystectomy alone, but this difference was not statistically significant. While increased toxicity was observed with the addition of MVAC, no chemotherapy-related deaths occurred, and surgical complication rates did not differ between the two arms. A phase II study with a dose-dense version of MVAC given in 2-week cycles with growth factor support yielded a similar pathologic complete response rate, and the regimen was well tolerated. Another randomized trial evaluated neoadjuvant CMV (cisplatin, methotrexate, and vinblastine) prior to local therapy versus local therapy. Overall survival at 10 years was improved significantly by 6% with neoadjuvant CMV. Gemcitabine and cisplatin have only been studied retrospectively as neoadjuvant chemotherapy, but reports suggest similar pathologic complete response rates and survival data. A meta-analysis including 3005 patients with T2 to T4a urothelial carcinoma from 11 trials reported a significant survival benefit for patients treated with neoadjvuant platinum-based combination chemotherapy equivalent to a 5% absolute improvement in survival at 5 years.

Despite data demonstrating both its feasibility and its efficacy, few patients are considered for neoadjuvant chemotherapy. Studies suggest rates of its use as low as 17% among patients with T2 or greater disease, even at academic centers. We typically recommend neoadjuvant chemotherapy for all patients with muscle-invasive urothelial carcinoma who are undergoing cystectomy and are appropriate for platinum-based chemotherapy, consistent with National Comprehensive Cancer Network (NCCN) bladder cancer guidelines.

2. Despite your recommendations, this patient opts to undergo surgery without neoadjuvant chemotherapy. His radical cystectomy pathology is notable for extension through the bladder wall, and two lymph nodes are positive for malignancy. His urologist now refers him back to you for consideration of adjuvant chemotherapy. His postoperative course was complicated by pneumonia, and as a result he became deconditioned and required a stay in an extended care facility. He presents today several weeks postoperatively, and he states that he is nearly back to his preoperative baseline. In regard to adjuvant chemotherapy, which of the following is true?

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