The MRC/EORTC Neoadjuvant Chemotherapy Trial for Advanced Bladder Cancer
October 1, 1999 4 minutes read
The MRC/EORTC Neoadjuvant Chemotherapy Trial for Locally Advanced Bladder Cancer
Abstracts & Commentary
Synopsis: Patients with locally advanced bladder cancer were randomly assigned to three cycles of chemotherapy with cisplatin, vinblastine, and methotrexate (with folinic acid rescue) or no chemotherapy before cystectomy or radiation therapy. Patients who had received chemotherapy had a slight survival advantage (5.5% at 3 years) and the median survival was 44 months compared to 37.5 months for the no-chemotherapy group.
Sources: Medical Research Council Advanced Bladder Working Party, Lancet 1999;354:533-540; Bartelink H, et al. Lancet 1999;354:526-527.
Several published reports of nonrandomized trials suggest that using preoperative chemotherapy improves disease-free and overall survival for patients with locally advanced bladder cancer. The current, large-scale, multigroup study was designed to determine whether the addition of neoadjuvant chemotherapy would enhance survival when compared to radical surgery or radiation therapy. Patients with locally advanced transitional cell carcinomas of the bladder (T2 G3, T3, T4a; N0-NX; M0) undergoing curative cystectomy or full-dose external beam radiation therapy (with curative intent) were randomly assigned to receive neoadjuvant chemotherapy (cisplatin, vinblastine, and methotrexate with folinic acid rescue) (n = 491) or no chemotherapy (n = 485). Tumor response was assessed cystoscopically before surgery or radiation therapy in most cases and patients were examined at six-month intervals for local, regional, and distant metastatic disease.
The median follow-up of patients was 4.0 years. By that time, 485 patients had died and the great majority of the deaths (78.6%) were due to the bladder cancer. The chemotherapy mortality was 1% and operative mortality was 3.7%. At three years, the difference in survival between the two groups was 5.5% (55.5% for the chemotherapy arm and 50.0% for the no-chemotherapy arm; 95% CI -0.5 to 11.0, P = 0.075). Median survival was 44 months for the chemotherapy group and 37.5 months for the no-chemotherapy group. Approximately one-third of the chemotherapy patients did not have demonstrable tumors at the time of cystectomy (i.e., local complete response). Thus, three cycles of neoadjuvant chemotherapy were associated with significant morbidity and a 1% mortality, but only marginal improvement in survival. The authors of the Medical Research Council report suggest that further modifications to this approach be examined and that neoadjuvant chemotherapy for locally advanced bladder cancer be considered experimental and not yet suitable for general application.
Commentary
Critics of this large, multigroup study might point to the chemotherapy chosen or the schedule and doses of drugs as an explanation for the results from neoadjuvant chemotherapy (grade 3 or worse leukopenia was noted in only 16% of patients). Furthermore, 20% of the patients assigned to the chemotherapy arm did not receive three cycles of chemotherapy and nearly 6% of patients received no assigned chemotherapy. It is discouraging to see such a modest effect (15% decrease in risk of death), if there is an effect at all (0 is within the 95% confidence limits), of aggressive, cisplatin-based neoadjuvant therapy in a population of patients that would be predicted to benefit on the basis of prior Phase II studies. One such trial demonstrated a 63% response rate, and in another, the response rate was 73%.1,2 This sequence of optimistic Phase II reports followed by more realistic large randomized trials is not uncommon in oncology, and particularly in analysis of neoadjuvant therapy. For example, neoadjuvant therapy for head and neck cancer seemed extremely promising based upon early, small trials, but experience in the larger randomized studies has tempered enthusiasm.3 It remains unclear whether these differences are an indictment of the therapies or of the clinical trials system. Medical oncology is in need of the kind of patterns of care study that the radiation oncologists have successfully undertaken.
There are some positives to be drawn from the current trial. Primary tumors responded well to the chemotherapy (32.5% complete response at the time of cystectomy), indicating once again the responsiveness of transitional cell carcinoma to the selected drugs. However, the absolute difference in three-year, locoregional, disease-free survival was only 5%. Subgroup analysis suggested that patients with higher tumor grades and better renal function derived significantly more benefit from the chemotherapy. Perhaps another study could be mounted to specifically address patients with more aggressive histology, a group that usually constitutes the majority of patients. It may turn out that neoadjuvant chemotherapy in this setting will increase the fraction of patients manageable with bladder preservation, although other approaches such as partial resection and external beam radiation are also promising in this regard.4
Neoadjuvant therapy is given with the goal of eradicating microscopic metastatic disease earlier, rather than later, in the treatment scheme. The strategy appears to be sound, but the method of accomplishment has not yet been optimized. Thus, it is hard to disagree with these findings in concluding that further studies are required before neoadjuvant chemotherapy for locally advanced bladder cancer becomes the standard of care.
References
1. Scher HI, et al. J Urol 1988;139:470-474.
2. Sternberg CN, et al. Cancer 1989:64:2448-2458.
3. Chan AT, et al. Curr Opin Oncol 1998;10:219-225.
4. Shipley WU, et al. Int J Radiat Oncol Biol Phys 1997; 39:937-943.
Which of the following statements about neoadjuvant chemotherapy for locally advanced bladder cancer is true?
a. Local response rates are high and at the time of surgery approximately one-third of patients will have no demonstrable disease.
b. Morbidity associated with chemotherapy is likely to be high, but there is a 30% survival difference at three years and it warrants widespread use of this treatment strategy.
c. Chemotherapy produces sustained, complete responses that may preclude the need for surgery or radiation therapy.
d. Chemotherapy reduces the local tumor to the extent that bladder saving surgery was made possible for approximately one-half of the patients treated.
e. Chemotherapy appears to work best in patients with low tumor grade and poor renal function.
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