Potential Role of Vinflunine in Two-tiered Treatment Strategies – Perioperative and Maintenance Therapy

European Oncology & Haematology, 2013;9(Suppl. 1):8-12

The potential role of vinflunine in sequential treatment strategies for urothelial carcinoma, in both the perioperative setting and maintenance therapy, will be highlighted below.

Rationale for Perioperative Systematic Therapy in Bladder Cancer
The natural history and evolution of urothelial carcinoma suggests that the study of perioperative systemic therapy may yield benefits (see Table 1),1–9 because 20–50 % of patients experience distant recurrence, and 5–15 % have locoregional recurrence.

The gold standard for patients with muscle-infiltrating disease is cystectomy. However, when comparing cystectomy series, survival is strictly related to the invasion of the bladder wall (see Table 1). The probability of non-recurring and organ-confined disease is approximately 80–90 %, while in patients with extravesical invasion it drops to 60 % and to 30 % in patients with nodal involvement after cystectomy. These figures explain why perioperative chemotherapy is an attractive option. Based on good responses obtained in advanced disease, chemotherapy is shifting to the neoadjuvant setting.

Long-term results of radical cystectomy in the treatment of invasivebladder cancer were presented by Stein et al. in 1,054 patients. Increasing tumour stage and nodal involvement were associated with significantly higher recurrence rates and worse overall survival (OS) (p<0.001). Specifically, patients with extravesical disease or lymph node positive (LN+) disease had a higher risk of recurrence compared withpatients who had organ-confined disease. The 10-year OS for patients with extravesical bladder tumours was 27 %. In patients with LN+ disease the OS at 10 years was 23 %. Respective recurrence-free values were 47 % and 31 %.5 These data provide a strong biological rationale for perioperative systemic therapy in bladder cancer.

Neoadjuvant or Adjuvant Therapy in Invasive Bladder Cancer
Several unanswered questions arise when gauging perioperative treatment options and the timing of cystectomy in patients with invasive bladder cancer. For instance, should radical cystectomy be performed without delay or is neoadjuvant chemotherapy a valid strategy? Should cystectomy be performed regardless of chemotherapy? Should the bladder be preserved and cystectomy be delayed according to chemotherapeutic response? Should adjuvant chemotherapy be administered, and if so, which regimen would be the most suitable?

Neoadjuvant Chemotherapy
Based on the encouraging results obtained with cisplatin combination chemotherapy regimens in patients with advanced, metastatic disease, use of neoadjuvant chemotherapy has been advocated to improve survival in patients with micrometastatic disease, and second,to preserve the bladder. It is thought that therapy may be better tolerated in patients upfront prior to cystectomy. On the other hand, neoadjuvant chemotherapy may make surgery more challenging and increase post-operative complications. A malignancy that is resistant to neoadjuvant chemotherapy may progress due to delay of surgery. Other disadvantages associated with neoadjuvant chemotherapy include difficulties in assessing response, and the fact that staging is based on clinical rather than pathological criteria. Benefits obtained in some studies are not reproducible. Only meta-analyses allowed to show a survival benefit ranging from 5 to 7 % (see Table 2).

Almost all neoadjuvant chemotherapy trials were negative, except for that conducted by the Southwest Oncology Group (SWOG) in 317 patients,which compared methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) followed by cystectomy versus cystectomy alone. The median survival for patients treated with neoadjuvant MVAC was 77 months compared with 46 months in patients treated with cystectomy alone (p=0.06). Respective 5-year survival was 57 % versus 43 %. The results achieved borderline statistical significance due to a long accrual and follow-up period. Patients treated with surgery alone had a 33 % greater risk of death compared with those treated with combination therapy (hazard ration [HR]=1.33, 95 % confidence interval [CI] 1.00 to 1.76).8 These data strongly support the argument that neoadjuvant chemotherapy followed by radical cystectomy should be further investigated as an approach to optimise muscle-invasive bladder cancer treatment.

A subsequent retrospective analysis showed that patients who underwent neoadjuvant chemotherapy and successful surgery, having had more than 10 lymph nodes removed, had a 5-year survival of 81 %, whereas patients who did not receive neoadjuvant chemotherapy and had fewer than 10 lymph nodes removed had a 5-year survival of 39 %.15 Surgical factors, therefore, have a considerable impact on bladder cancer outcome, and many factors are determinant for survival (see Table 3). The quality of surgery cannot be underestimated.

The largest neoadjuvant chemotherapy randomised trial was performed in 976 patients with T2–T4 muscle-invasive N0 urothelial cancer.10 Patients were randomised to three cycles of cisplatin, methotrexate and vinblastine (CMV) versus no CMV, followed by either cystectomy or radiotherapy local treatment that was left to the investigator’s discretion. When first published in 1999,16 the data did not reach statistical significance, but at 7 years of follow-up, a 6 % survival difference in favour of patients treated with neoadjuvant CMV was reported, and the results reached borderline significance (HR=0.85, 95 % CI 0.72–1.00; p=0.048).11 With a longer follow-up of 10 years (median follow up of 8 years), the 6 % survival difference was maintained with neoadjuvant CMV (HR=0.84, 95 % CI 0.72–0.99; p=0.037).17

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