ALA-PDD is not only for diagnosis, but also plays an assistive role for surgical resection by identifying the tumor range. As described above, the standard treatment for NMIBC is TURBT. In TURBT, additional resection under navigation of ALA-PDD fluorescence can avoid insufficient resection of tumors (see Video 30.2), reducing the rate of postoperative intravesical recurrence.

Regarding the recurrence-free survival rate, Denzinger et al. [18–20] compared the intravesical recurrence rate after TURBT over a long-term follow-up for a maximum of 8 years involving 191 bladder cancer patients. The recurrence-free survival rates after PDD-TURBT were significantly and consistently higher than that after conventional TURBT. They also performed multivariate analysis employing the Cox proportional-hazards model, in which the hazard ratio of PDD-TURBT was 0.29 (95 % confidence interval: 0.15–0.56, p = 0.0002), showing that PDD-TURBT was an independent prognosis-improving factor related to intravesical recurrence. In our clinical experience [13], the recurrence-free survival rate over a median duration of follow-up of 22 months (0.2–68.7 months) in 99 non-muscle invasive bladder cancer patients was 86.9 % after 12 months, 74.7 % after 24 months, 69.7 % after 36 months, 67.7 % after 48 months, and 66.7 % after 60 months, showing that the rate was significantly increased compared to that after conventional white light TURBT. We also performed multivariate analysis employing the Cox proportional-hazards model. The hazard ratio of PDD-TURBT was 0.578 (95 % confidence interval: 0.371–0.888, p = 0.012), showing that PDD-TURBT was an independent prognosis-improving factor related to intravesical recurrence. Moreover, meta-analysis and systematic review showed less residual tumor and improve recurrent-free survival but not progression-free survival in randomized trials of ALA-PDD (see Table 30.1) [14–17].

In ALA-PDD, adverse events, such as phototoxic reactions, mainly photosensitive dermatitis, and liver disorder, induced by previous photosensitive substances, such as hematoporphyrin mixtures and porphyrin derivatives, is of the most serious concern. However, as described above, ALA is a natural amino acid contained in animals and plants, and it is less toxic, highly cancer-specific, and rapidly metabolized and excreted by normal cells. When ALA was systemically administered orally, the administered ALA was mostly eliminated from plasma after 6 h and excreted from the body after 24 h [21]; whereas, when ALA was administered into the bladder, the maximum plasma level of the predisposing cause of ALA-induced adverse events, protoporphyrin IX (PpIX), about 30 min after intravesical administration was about 1/100 of that after oral administration, and the half-life was also short (about 54 min) [22]. It is pharmacologically impossible for these conditions to cause phototoxic reactions, mainly photosensitive diseases, and liver disorder.

Actually, no photosensitive dermatitis developed, requiring no protection from light, in not only these pharmacological verifications but also an intervention study reported by Filbeck et al. [23], in which patients treated with intravesically applied ALA underwent experimental ultraviolet light irradiation, and a study involving the largest number of bladder cancer patients diagnosed by PDD using ALA (1,713 applications in 875 patients). In our clinical experience involving the 210 bladder cancer patients [13], although no special precaution, such as liver support and light shielding, was implemented throughout PDD, bladder irritation symptoms, such as pollakiuria and urgency, were observed after intravesical ALA administration in 17.3 %, photosensitive diseases after oral ALA administration in 4.4 %, elevation of blood liver enzyme levels [Aspartate Aminotransferase (AST), Alanine Amino-transferase (ALT)] in 3.0 %, and nausea/vomiting in 3.0 %, but all of these events were mild and transient, and no serious adverse event occurred.