Why consider neoadjuvant chemotherapy for muscle-invasive transitional cell carcinoma of the bladder?

Abstract

The Canadian Cancer Society estimates that in 2007 there will be 6600 new cases of transitional cell carcinoma of the bladder (TCCB) and 1750 deaths.1 Twenty to thirty percent of new patients will have muscle-invasive disease, and even with aggressive surgery such as radical cystectomy, it is expected that up to 50% of these patients' cancers will recur.2 Death from TCCB in these patients is generally due to distant metastases. Therefore, the use of systemic therapy in conjunction with good local control is essential to improve cure rates for muscle-invasive disease. Chemotherapy can be given either preoperatively (neoadjuvant) or postoperatively (adjuvant). In some malignancies, there are compelling reasons to sequence various treatment modalities in a particular order, such as neoadjuvant chemotherapy in large breast cancers to downstage the tumour and facilitate breast conserving surgery. In other malignancies, this order is reversed, with the surgery achieving local control and establishing a histological diagnosis before giving systemic treatment. TCCB is a chemosensitive disease, with response rates ranging from 50% to 70% with the use of cisplatin-based regimens in the metastatic setting.3,4,5 However, this means that many patients will not respond to chemotherapy. The use of neoadjuvant chemotherapy allows for an in vivo chemosensitivity trial. Patients can be imaged mid-way through the treatment to see if they are responding. Responders can complete their course of treatment and nonresponders can abandon chemotherapy and go immediately to surgery. If one treats in the adjuvant setting, there is no disease to follow on imaging since it has been resected, so all patients must complete a full course of therapy even though not all will benefit. Preoperative chemotherapy may also downstage patients before surgery. In the landmark neoadjuvant trial by Grossman and colleagues6 it was demonstrated that neoadjuvant chemotherapy using methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) rendered 38% of patients pathologically free of disease at cystectomy; and the 5-year survival of this group was 85%, which is significantly better than what would be expected for all comers with muscle-invasive TCCB. However, the major goal of neoadjuvant chemotherapy is not local control but early treatment of micrometastatic disease, which if left untreated may develop into incurable disease. Neoadjuvant chemotherapy targets micrometastatic disease while the disease burden is smallest, giving the chemotherapy the best chance to be effective. Theoretically, delaying chemotherapy until adequate postoperative healing has occurred allows the systemic disease to grow in the interim. Patients may also tolerate chemotherapy better before surgery, allowing them to receive the full course of treatment and thus all the benefits it can offer. Finally, the most compelling reason to give neoadjuvant chemotherapy for TCCB is that, unlike chemotherapy in the adjuvant setting, there is good evidence of a survival benefit for this approach.