Ask the Doctor

Fall 2009

Our question for this issue of Outlook is answered by Dr. Deborah Bradley, Assistant Professor of Medicine, Duke University Medical Center. We sincerely appreciate Dr. Bradley sharing her expertise regarding systemic chemotherapy.

Q:  For a patient who is going to have a radical cystectomy for invasive bladder cancer, when is systemic chemotherapy appropriate?  Should chemotherapy be given prior to the surgery or following the surgery?  What are the pros and cons of each approach?

The goal of radical cystectomy (surgical removal of the bladder) is to provide definitive treatment for patients with high-risk bladder cancer.  In patients with muscle invasive disease, long term survival with cystectomy alone is only 30-80% depending on stage and other prognostic factors.  Investigators have studied adding chemotherapy before cystectomy (neoadjuvant) or after cystectomy (adjuvant) to improve outcomes.

There are several potential advantages to each approach.  Neoadjuvant chemotherapy has the advantage of immediately treating micrometastatic disease (cancer cells outside the bladder that are not large enough to be seen in scans) rather than waiting for recovery from cystectomy.  Additionally, chemotherapy is better tolerated and drug delivery has been shown to be better prior to surgery.  Since the primary tumor is still in place, it can be monitored and chemotherapy discontinued if there is evidence of disease progression.  Information on how sensitive your tumor is to chemotherapy can be helpful to your doctor when making any future treatment decision.  Cons to this approach include the fact that there is a subset of patents in which neoadjuvuant chemotherapy is ineffective.  If you are one of these patients, neadjuvant therapy delays the potentially curative therapy of cystectomy.  The biggest advantage to adjuvant therapy is that we can use the pathology results from the bladder and lymph nodes removed during cystectomy to better select patients for chemotherapy who are at highest risk for recurrence.   Additionally, with adjuvant therapy there is no risk from delaying cystectomy.

Although both are reasonable options to consider, neoadjuvant chemotherapy has stronger evidence from clinical trials supporting its use.   In a large randomized phase III trial (317 patients from 126 institutions) cystectomy alone was compared to three cycles of MVAC (methotrexate, vinblastine, adriamycin, cisplatin) followed by cystectomy.  There was a 25% decreased risk of death in patients treated with neoadjuvant chemotherapy without an increase in the risk of death or complications related to surgery.  As a result, neoadjuvant chemotherapy followed by cystectomy with lymph node dissection has become the standard of care at many institutions for patients with muscle invasive bladder cancer.

Although MVAC is the standard neoadjuvant chemotherapy regimen, many patients are treated with a combination of GC (gemcitabine, cisplatin).  This is because in metastatic bladder cancer, the combination of GC has been shown to work as well as  MVAC with less toxicity and fewer side effects.  It is assumed this is also the case in the neoadjuvant setting. Additional support for cisplatin-based neoadjuvant chemotherapy comes from a meta-analysis of data from patients enrolled in 11 different clinical trials.  Analyzing the data from all 3005 patients showed a survival advantage for patients treated with neoadjuvant platinum-based combination therapy.

Although many patients with muscle invasive bladder cancer are treated with adjuvant therapy, the data supporting this approach is much weaker.  The adjuvant trials have been smaller and have been criticized for methodological flaws limiting interpretation of results.  In order to try to get around these limitations, data from many of these trials has been analyzed together in a meta-analysis of 491 patients from six trials.  This meta-analysis did show a 25% relative reduction in risk of death with adjuvant therapy.

Despite the pros and cons of neoadjuvant and adjuvant chemotherapy, I believe neoadjuvant cisplatin-based combination chemotherapy followed by cystectomy with lymph node dissection should be the standard of care for treatment of muscle-invasive bladder cancer.  In my opinion, chemotherapy should be offered before cystectomy to all patients who are thought to be able to tolerate cisplatin.  Additionally, adjuvant chemotherapy should be offered to patients who have not received neoadjuvant chemotherapy but whose postoperative pathology finds tumors that extend outside the bladder or positive lymph nodes.