Page 8 - Management of non-muscle invasive bladder cancer

cUa guidelines

Treatment schedule BCG and 1-year and 3-year maintenance. Oddens and
colleagues showed that a 3-year maintenance of full-dose
• Full dose of induction BCG and 3-year maintenance is BCG had superior recurrence-free rates without increased
recommended for patients with high-risk NMIBC who toxicity. No differences in progression or overall survival
can tolerate intravesical therapy with dose reduction were demonstrated. Risk stratification demonstrated that
reserved for cases of BCG intolerance (Grade B rec- patients with high-risk NMIBC achieved maximal benefit
ommendation). when treated with full-dose BCG induction followed by
3-year maintenance. However, patients with intermediate-
BCG is given 2 to 4 weeks following TURBT to avoid system- risk did not achieve further improvement beyond the full
ic side effects. Optimal treatment schedules have not been dose BCG induction and 1-year maintenance. Based on
123
established, but there is an agreement that only 6 weekly the above data, we recommend the Lamm protocol with
inductions are not sufficient. In patients who received BCG full-dose induction BCG and 3-year maintenance be given
117
induction only, a second induction course has an additional to patients with high-risk NMIBC who can tolerate intravesi-
benefit of about 25% when used for prophylaxis and 30% cal therapy, with dose reduction reserved for cases of BCG
when used for CIS (Level of Evidence 3). 117,118 There is suf- intolerance (Grade B recommendation).
ficient evidence that BCG maintenance in addition to induc- The addition of interferon to BCG in the treatment of
tion confers reductions in both recurrence and progression BCG-naïve patients in a large multicentre prospective
(Level of Evidence 1). Lamm and colleagues randomized randomized study yielded no benefit compared to BCG
patients with intermediate and high-risk NMIBC to receive alone. 124 However, in a recent randomized prospective trial
6 weekly inductions with BCG versus 6 weekly inductions from Singapore (unpublished) that was presented at the AUA
followed by maintenance (3 weekly cycles at 3 months meeting in 2014, superiority of BCG plus interferon when
and 6 months, then every 6 months up to 36 months). 119 compared to BCG alone was demonstrated. At the present
125
Patients receiving maintenance showed improved median time, it remains controversial as to whether adding interferon
recurrence-free and worsening-free survival. In a meta- to BCG improves efficacy in BCG naïve patients.
analysis of 24 trials with 4863 patients, Sylvester and col-
leagues showed a demonstrated superiority of BCG over BCG toxicity
107
intravesical chemotherapy. Progression-free survival was
improved only in patients who received maintenance BCG. BCG toxicity most commonly occurs in the first year of
Similarly, Bohle and colleagues had similar conclusions in therapy. 126 The effect of BCG dose on toxicity is unclear.
their meta-analysis of 9 trials, in which 1328 patients with According to the CUETO (Club Urolo´gico Espan˜ol de
NMIBC treated with adjuvant MMC were compared with Tratamiento Oncolo´gico) study, a reduction in dose was
1421 patients treated with adjuvant BCG. 108,109 With a medi- associated with a decrease in the side effects of the drug;
an follow-up of 26 months, recurrence rates were 46.4% however, in the EORTC study, this association was not
for patients treated with adjuvant MMC versus 38.6% for observed when comparing full-dose to one-third-dose instil-
those treated with adjuvant BCG; progression rates were lations. 127-129
9.4% for patients treated with adjuvant MMC versus 7.7% Some studies suggest that prophylactic antibiotics given
for those treated with adjuvant BCG (p = 0.08, OR 0.77). after intravesical BCG instillation may decrease the rate or
When only trials using maintenance were included (5 tri- severity of adverse events without a significant decrease in
als), the difference was significant (p = 0.02, OR 0.66). The efficacy. 130,131 However further clinical research is needed to
authors concluded that at least 1 year of maintenance BCG assess whether antibiotics usage with BCG can affect tumour
was required to show superiority of BCG over chemotherapy progression by impairing the efficacy of BCG. Common and
in decreasing recurrence or progression. uncommon side effects of BCG and their management are
The optimal BCG dose and maintenance schedule has summarized in Table 1. 132,133
not been clearly identified. Several European studies have
demonstrated that the BCG dose can be reduced to one-third BCG failure
or one-quarter with a reduction in toxicity but comparable
efficacy. 120-122 However, Morales and colleagues have shown • In patients with BCG-refractory high-risk NMIBC, radi-
that dose reduction is associated with decreased efficacy cal cystectomy is recommended (Grade B recommen-
in North American patients; they hypothesize that a lower dation).
immune response may be induced in patients with no pre- • In patients with BCG relapse, BCG plus interferon,
vious exposure or inoculation with tuberculosis. Recently, gemcitabine, or re-induction with BCG are valid
a randomized trial of 1355 patients with intermediate and options when patients are not suitable for or refuse
high-risk NMIBC compared full-dose and one-third dose radical cystectomy (Level of Evidence 3).

CUAJ • September-October 2015 • Volume 9, Issues 9-10 E697