Indication & Results of PDD for Bladder Carcinoma
The most important indication from the beginning of PDD was the improvement of the detection of CIS. Since the discovery that highly aggressive CIS is mostly inconspicuous in white-light by Meyer M Melicow (1895–1983) in 1952, even a well-experienced surgeon in conventional cystoscopy cannot exclude the existence of a malignant lesion despite the absence of papillary tumors.[41] This circumstance led to several attempts to increase the detection of bladder carcinoma, including CIS, by TURBT. After the introduction of random biopsies with inconsistent prognostic value in the mid-1990s, PDD became an approach for better tumor detection.[20,42] In high-risk NMBC patients, as well as intermediate- and low-risk disease, PDD was shown to significantly reduce the recurrence rate.[43]
Sensitivity & Specificity of PDD, Residual Tumor Rate & Recurrence-free Survival
The relatively low specificity of PDD was its main critical point, especially in the early clinical use.[34] The fact that not only tumors, but also regenerating and inflammatory cells show fluorescence by PDD leads to a high rate of false-positive findings. While sensitivity under fluorescence-guided TURBT was in nearly all studies concerning 5-ALA and HAL, over 90% (up to 97% in two independent analyses by Zaak et al. and Grimbergen et al.) and so much better than conventional white-light (maximum of 84%), specificity is a point of weakness with PDD.[44–47] With 5-ALA, specificity was between 35 and 67%, corresponding to data under Hexvix.[48–51] In a current analysis by Burgués et al. on a NMBC Spain collective, a specificity of 82% was observed, but this was even worse than white-light TURBT in 91%.[50] The better specificity of white-light TURBT is easy to understand because of the lower number of lesions visible under conventional cystoscopy compared with PDD. Concerning the fact that the problem of nonmuscle-invasive bladder carcinoma is not the papillary pTa tumor, but the early invasive, not seldom solid, pT1 BC and especially the flat CIS lesion, a higher percentage of false-positive resected areas is acceptable owing to a much higher detection rate of the 'problem' lesions of nonmuscle-invasive bladder cancer. Therefore, CIS overdetection with PDD reaches up to over 200% compared with white-light TURBT.[50]
Owing to this problem, parameters other than sensitivity and specificity for evaluating PDD needed to be analyzed. The first prospectively randomized studies from the mid-1990s onwards dealt with the standardized determination of remaining tumor tissue (residual tumor rates) within the framework of second resections under conventional white-light, carried out 6 weeks after initial TURBT. In terms of the PDD, these studies are most comparable, especially in the agent, that was in nearly all analyses in the early years of PDD 5-ALA.[51–57] In later studies, the approved agent HAL was tested.[50,58,59] The further treatment of patients was also equal regarding the existing guidelines of the established international associations of urology. The most important differences existed in the patient collectives that often enclosed all stages of NMBC, but were also limited in some analysis to subgroups of NMBC, for example, pT1 BC or CIS.[43,60] Although in study procedures the method of TURBT is defined, differences in the extent of bladder tumor resection exist and are not completely distinguishable, even in the prospective randomized studies (see Table 1).
Filbeck et al. demonstrated the most impressive data on the positive effect of PDD on bladder tumors. After conventional TURBT, tumors remained in over 25% of cases, whereas after fluorescence diagnosis, there were only 4%.[51] This tendency was confirmed by other studies, with reduction of residual tumor rates of approximately 20–23%.[52,53] No statistically significant improvement of residual tumor rates were later found by Alken et al., with an overall residual tumor rate of 29% in second resection. The analysis was only published as congress abstract.[54]
In general, it became obvious that complete resection of bladder tumors with fluorescence diagnosis was proven by the decreased number of residual tumors in second resection and seems to be more efficient than conventional TURBT. However, in order to prove the clinical value of the method, it was necessary to demonstrate whether the recurrence rate of bladder cancer could be reduced with PDD as well. Two groups published their recurrence-free survival rates by conventional and PDD. Daniltchenko et al. demonstrated a 5-year recurrence-free survival rate of 41% after PDD compared with 25% after conventional TURBT.[55] Denzinger et al. even reported a 26% difference in 8-year recurrence-free survival rate (71 vs 45%) in the largest study collective.[56] On the same patient set, Otto et al. could demonstrate that PDD was of advantage in all EORTC risk groups of nonmuscle-invasive bladder carcinoma. After a follow-up period of 100 months recurrence rates differed between 19 and 56% in PDD group and from 48 to 85% after conventional TURBT depending on low-, intermediate- and high-risk patients.[57] Burger et al. first compared results of PDD with 5-ALA and HAL, and found a 3-year recurrence-free survival of 80 and 82%, respectively, significantly better than under the conventional setting, which had recurrence-free survival of 67%. HAL showed slightly better results than 5-ALA without reaching statistical significance.[61] Hermann et al. reported recurrence rates after usage of Hexvix confirming these data with recurrence rates of 31% after PDD and 47% following white-light TURBT, Drãgoescu et al. presented a reduction of recurrence rate to 18% (compared with 45%).[58,59] While both groups studied PDD for stage Ta/T1 bladder cancer, Lerner et al. analyzed the detection rates of CIS by HAL finding an obvious advantage of PDD compared with white-light resection.[60] For detailed information, see Table 1.
The Value of PDD From an Economic Point of View
These days, new therapeutic strategies need to not only be effective, but also economical; this aspect of PDD was proved more so in recent years. Burger et al. presented a study on cost analysis of PDD for one of the biggest PDD patient collectives in 2007 using 5-ALA. The question was whether additional costs caused by fluorescence diagnostics could be compensated by a lower frequency of consecutive hospital stays owing to lower recurrence rates. In a single-center analysis the costs for the special technical equipment for fluorescence diagnosis and the single catheterization for 5-ALA administration amounted to €135 per patient per procedure. The costs for one conventional transurethral resection amounted to €1750, according to the German diagnose-related group health pricing system. Since, after PDD, only a third of the patient group needed further transurethral resection with proof of recurrence, an average of 1.32 resections per patient were needed after primary conventional tumor resection. The significant difference in the rate of second resections in this study compensated the additional costs of the method by far.[61] Using the same data, Otto et al. could demonstrate that PDD saved money even in low-risk patients over a study period of 8 years.[57] Other authors also assumed a better cost–effectiveness of PDD-guided TURBT.[22] Taking into account the annual costs of bladder cancer in the USA alone, of approximately $3 billion, there is a lot of potential for cuts in the health systems.[62]
Of course, before starting to use PDD, a clinic has to afford investments; for example, for the blue-light source and a special optic, that amounts up to approximately €5000.[61] However, in high-volume departments of urology, depending on the number of patients treated with PDD TURBT, these costs can be reimbursed quite quickly.
Future Oncol. 2011;7(9):1057-1066. © 2011 Future Medicine Ltd.
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