This study describes the efficacy of six weekly instillations of apaziquone after a complete ablative response for patients with intermediate- and high-risk NMIBC, with 2 years of FU.
In this study, the CR rate of 67%, 2–4 weeks after the last apaziquone instillation was superior to most marker lesion studies performed with other (neo-) adjuvant drugs (discussed in [7
]). A marker lesion study represents an excellent, safe method to test the ablative efficacy of a given treatment, with rates of progression to muscle invasive disease of <1% [12
]. Marker lesion studies are recommended before embarking on any prophylactic study to avoid treatment with an ineffective agent [13
]. Only three studies also report about ‘long-term’ drug efficacy in a small number of CR patients [15
]. Brausi et al. [15
], randomised patients with intermediate-risk NMIBC for either 40 mg of MMC or electromotive drug administration (EMDA)/MMC for 8 weeks, and obtained a CR in 41.6 and 40% of patients, respectively. Only two of five MMC-treated patients with a CR were recurrence-free after 11 months, and five of seven EMDA/MMC-treated patients with a CR after a mean FU of little more than a year. Newling et al. [16
], treated patients with refractory UCC with or without CIS of the bladder with six courses of 800 mg valrubicin, and obtained a histological CR in 18/39 (46%) patients. Their estimate of the mean time-to-recurrence was 248 days for CR and NR together, and 5 of 39 (12.8%) patients remained recurrence-free after the FU period of 2 years. Maffezzini et al. [17
], treated patients with low- and intermediate-risk NMIBC with 2,000 mg of gemcitabine for 4 weeks, and obtained a CR in 13 of 28 (46.4%) patients. Of the 28 (67.8%) patients, 19 experienced a recurrence within the first year. In comparison to other drugs used in marker lesion studies where also longer term FU was reported, the 2-year recurrence-free rate in our study (49.5% in the CR group and 39% in the whole group) represents a good result. The low percentage of recurrence-free patients from the reported marker lesion studies might be explained by the recruitment of patients with a high risk of recurrence: these patients obviously had multiple tumours, and often failed previous intravesical therapy.
We also calculated probabilities of recurrence according to the EORTC risk Table [3
], which were based on an analysis of 2,596 NMIBC patients who were treated between 1979 and 1989, but treatment of NMIBC at that time obviously differed from the current NMIBC guidelines [1
]. Twenty percent of patients from the analysis initially received no treatment, <10% received an immediate instillation of chemotherapy, a second-look TURBT was not performed in high-risk patients, and BCG was given without maintenance instillations. Therefore, the predicted recurrence and progression rates of the risk tables might be higher compared to current clinical practice. Nevertheless, the reported restrictions are by approximation also applicable to the patients in our study. For patients with a risk score of 1–4, 5–9 and 10–17, the corresponding probabilities of recurrence after 2 years are 34, 51 and 71%, respectively. In our study, the majority of patients (38 of 46, 82.6%) had a risk score of 5–9 (Table ) with a 51% probability of recurrence at 2 years of FU. The overall recurrence-free survival at 2 years FU after apaziquone treatment was 18/46 (39%). This seems to be worse than the predicted probabilities of recurrence by the EORTC. However, it is important to realise that most of our patients with NR underwent TURBT without further prophylactic treatment, which otherwise would have been given as part of current routine treatment and would have influenced clinical outcome. Furthermore, the failure of the NR patients to respond to at least one kind of intravesical therapy (in this case apaziquone) may increase the risk of recurrence for these patients. Therefore, the recurrence-free survival with prophylactic treatment is expected to be higher than 39%. Sub-analyses were performed between the EORTC recurrence score groups, but the 1–4 and 10–17 groups were too small to note any significant differences with regard to treatment response. Of note: ‘all’ five patients with a score of 1–4 had a CR to apaziquone treatment.
As discussed, it is difficult to compare our results with results from literature and the EORTC tables. It is difficult to predict whether the good CR-rate of 67% at 3 months FU also is an indication of a long-term effect in preventing recurrences. Apparently, the difference in recurrence-free survival between the CR and NR groups (Fig. ) is already present from FU month 6, which does not support an ongoing protective effect in CRs.