The Enlightenment of Bladder Cancer Treatment
Compared with prostate cancer, which exclusively affects male patients, urothelial bladder cancer is the most common urogenital carcinoma affecting both men and women. In approximately 75% of cases, bladder cancer occurs as multifocal nonmuscle-invasive papillary tumor that demonstrates high rates of recurrence, leading to frequent transurethral resections with the need of hospitalization. These cases have paved the way for photodynamic diagnosis. Since the 1990s, this technique has been used to identify bladder tumors, especially highly aggressive carcinoma in situ, in an easier and more complete way compared with conventional white-light cystoscopy. This article gives an up-to-date review of the method, indication and results of photodynamic diagnosis for treatment of urothelial bladder cancer.
Epidemiology & Etiology
With approximately 110,000 diagnosed urothelial bladder carcinomas per year, urothelial bladder cancer belongs to the ten most common neoplasms in Europe.[1] Bladder cancer is therefore the most frequent malignant tumor of the urogenital tract, affecting both men and women.[2] No regional preferences for developing bladder cancer are recognizable, with the highest incidence (>20 per 100,000 inhibitants) in Denmark, The Netherlands and Spain.[1] In the USA, the incidence of bladder cancer increased from seven to 11 per 100,000 inhibitants between 1997 and 2007.[3] In multiethnic countries, such as New Zealand for the European population, a two-fold higher incidence of bladder cancer is demonstrated compared with the Maori and Asiatic group.[4] There are two to three diseased males for every diseased female – this is mainly attributed to the fact that men are usually exposed to more risk factors of the urothelial carcinoma: they are more often smokers and more likely to be affected by harmful substances, such as in working life.[5]
Smoking tobacco is of great importance with regard to epidemiology, especially for the development of bladder cancer with an up to six-fold increased risk compared with a nonsmoker after approximately 60 pack-years (corresponds to smoking two packs of cigarettes each day over a period of 30 years); smoking cigars and pipes on a regular basis also increases the risk of developing bladder cancer 2.3- and 1.9-fold, respectively.[5] Even environmental tobacco smoke might be able to cause bladder cancer (1.4-fold risk increase).[6] It is debated whether and to what extent stopping tobacco smoking can normalize the personal risk of developing bladder cancer.[7–10] With cigarette smoke, as with most detected industrial substances, aromatic amines seem to be responsible for the development of cancer.
Clinical & Biological Characteristics
The typical characteristics of bladder cancer are multiple synchronous tumors (multifocality) and a tendency of recurrence.[11] In general, one distinguishes between papillary and flat lesions of the bladder whereby up to 85% of all tumors are strictly limited to the mucosa and subcutaneous tissue.[12] Approximately 15% of bladder tumors are already muscle-invasive at the initial diagnosis and lead to the initial removal of the bladder by radical cystectomy with a secondary urinary diversion.[13] In less than 5% of cases, a solitary carcinoma in situ (CIS) is diagnosed.[14] In general, this flat, strictly superficial lesion is a precursor of invasive disease with a worse prognosis that is difficult to differentiate macroscopically from normal urothelium.[15,16] Both papillary tumors and the CIS are characterized in up to two-thirds of the cases by several foci and high recurrence rates. Approximately 75% of all superficial bladder carcinomas recur within the first 5 years, up to a third of high-grade stage T1 tumors even demonstrate progression with the need for cystectomy.[17,18]
Not all recurrences are actually newly developed tumors, especially so-called early recurrences, which are often in fact residual carcinoma tissue remaining from the first surgery by transurethral resection of bladder tumors (TURBTs).[19] A single analysis, practicing special maneuvers, such as random biopsies in routineous reresections of extensive and undifferentiated bladder carcinomas, demonstrated a positive effect on cancer-specific survival, but there are no guidelines on how to take these biopsies in the correct manner.[14,20] The guidelines of the European Association of Urology recommend a single instillation of mitomycin C immediately after TURBT. Depending on certain histologies, for example, multifocality, tumor size over 3 cm and high grade carcinoma, 4–6 weeks after TURBT, a reresection is recommended.[14] According to the accepted guidelines, intravesical treatment with topic chemotherapy with mitomycin C or immunotherapy with Bacillus Calmette–Guerin (BCG) decrease at least the rate of recurrences.[21] However, due to the mentioned characteristics, nonmuscle-invasive bladder carcinoma (NMBC) is a ‘lifelong’ disease with high rates of resurgeries and hospital stays due to recurrence.[22] This circumstance made new approaches for bladder cancer detection necessary leading to the use of photodynamic diagnosis (PDD).
While NMBC demonstrates a good prognosis in general with a disease-specific survival of nearly 100%, muscle-invasive bladder carcinoma patients need radical treatment, either by radical cystectomy and lymph node dissection followed by urinary diversion (e.g., orthotopic neobladder or ileal conduit), or radiochemotherapy, especially for patients with severe comorbidities.[13] Stage T2 cancer, after appropriate treatment, has a survival rate of approximately 70%, decreasing to only 20% in the presence of lymph node metastases.[23,24] Patients with distant metastases are not curable and have to undergo chemotherapy (best results after cisplatin and gemcitabine) to improve their prognosis.[25] Stage T1 NMBC has an individual role in bladder cancer. Shahin et al. demonstrated that this stage – although nonmuscle-invasive – might have contradictive outcomes with a third of patients dying of bladder cancer, a third undergoing radical cystectomy and a third never recurring.[17] This circumstance makes the necessity of improved transurethral diagnosis and therapy obvious.
Transurethral Resection & PDD
Development of Transurethral Resection of the Bladder as Gold Standard
In the 1880s, Bernhard Bardenheuer (1839–1913) advised, in cases of uncertain diagnosis, explorative incision in patients with suspect of bladder tumors. A contemporary witness of the surgeon, Maximilian Nitze (1848–1906), found a remedy in his invention of an optical device for urethrocystoscopy, published in 1877: because of the first cystoscopy and the rapid development of the device into a surgical cystoscope, the open-surgical operations were replaced with transurethral resections from the end of the 19th Century onwards. In 1885, the Viennese dermatologist, Josef Grünfeld (1840–1912), used this new surgical procedure for the first time.[26] Even then, when urology did not yet exist as a medical speciality, dermatology, as the speciality that mainly treated urogenitaly tract diseases, was a pioneer in the treatment of bladder cancer. The advantages of the new technique were obvious, therefore, representatives of open surgery rapidly acknowledged the importance of Nitze’s invention. As early as 1880, Bernhard von Langenbeck (1810–1887) looked positively ahead at endoscopic diagnosis and treatment of urogenital tract diseases in a lecture on surgery.[26]
Galvanic cautery, the treatment of tumors with heat, was replaced with electroresection at the beginning of the 20th Century. Edwin Beer (1876–1938) successfully used this method with tumors of the bladder for the first time in New York in 1910. The method spread very quickly all over the world and, owing to advancements, for example, the use of diathermy and the invention of the foot switch, became an unrivalled device for treating tumors of the urinary tract. From the 1930s onwards, systematic TURBT was established, which has been further developed ever since. Technically advanced cystoscopes and not least photodynamics, to name just the most important aspects, have further increased the significance of TURBT for the diagnosis and treatment of bladder cancer.[26]
Origins of PDD
Even in ancient times, people knew the curative effect of certain substances under light irradiation. At the end of the 19th Century, this phenomenon was used clinically for the first time, especially for the therapy of cancerous and infectious skin diseases.[27] Besides medicine, in particular dermatology, it is especially owing to physics and chemistry that the mechanisms of ‘photodynamics’ are well known today: a photosensitizing substance or its components are accumulated in diseased cells and are made to fluoresce under light of a certain wavelength.[27]
The significance of light for general well-being and health in particular was understood at an early stage. While the relevant papyri of ancient Egypt (2nd millennium BC) and the Corpus Hippocraticum (5th Century BC) described the influence of sunlight in connection with different medications, Arab medicine is considered to be the first medical science that consciously used photosensitive substances together with sunlight for therapy. Over the centuries, new insights into the physics of light, such as the discovery of infrared and UV light by Friedrich W Herschel (1738–1822) and Johann W Ritter (1776–1810) in the year 1800, formed the basis for the modern application of light in medicine.[27] After it was discovered that UV light is responsible for sunburns and its bactericidal effect could be proven, the practical use of UV light in the treatment of skin diseases quickly began in the late 19th Century. Niels R Finsen (1860–1904) raised attention to the new technique by the successful therapy of tuberculosis of the skin (lupus) with the carbon arc lamp and was awarded the Nobel Prize in Medicine in 1903.[27] Of course, treatment of dermatological diseases, for example, psoriasis, by UV light is not to be mixed with the photodynamic therapy that is always a combination of light and an applicated agent.
For development of PDD and photodynamic therapy, parallel to the discovery of the effect of sunlight, the insights into the enhancement of this effect through certain substances was essential. As is often true in science, coincidence played an important role. Parallel to the first attempts in light therapy, it was observed that animals developed skin rashes after eating certain plants, such as St John’s Wort, depending, on the one hand, on their coat color and, on the other hand, on the intensity of solar radiation.[27] Similar occurrences were observed with an epilepsy patient after the intake of dye containing eosin, which soon led to attempts to make this systematically usable for patients. The research of the pharmacologist Hermann V Tappeiner (1847–1927) was the basis for the systematic use of the method that was called ‘photodynamic reaction’ by the discoverers.[28] It is obvious that dermatological diseases, such as skin cancer, tuberculosis or syphilis, were then successfully treated with eosin. While searching for more effective substances, hematoporphyrin was investigated from 1912 onwards, a degradation product of the red blood pigment, which led to severe phototoxic reactions after intravenous test injection and light exposure.[29] Today, both eosin and porphyrin are used for photodynamic therapy for many indications not only for dermatological diseases, but also for benign and malign diseases of the lung, heart, genitourinary tract and ophthalmology.[27] In the 1940s, researchers found out that this substance could also be used for diagnostic purposes when different study groups noticed the red fluorescence of tumor tissue through porphyrin. However, owing to severe side effects, the substance was considered unsuitable for a long time; only the use of porphyrin precursor, 5-aminolevulinic acid (5-ALA), could be safely used in the diagnosis of photosensitive tumors.[27]
Introduction of PDD in the Treatment of Urothelial Bladder Carcinoma
Since the 1960s, there have been approaches to make pathological findings of the bladder mucosa more easy to discover, with the help of substances that were filled into the bladder. However, early labeling studies with methylene blue and tetracycline demonstrated disappointing results. Just like in dermatology, research soon focused on photosensitive substances.[30] Although systematically administered hematoporphyrins demonstrated good accumulation in malignant tissue under light at a wavelength of 630–690 nm, insufficient opto-technical prerequisites and phototoxic skin reactions, such as severe side effects, were obstacles to in vivo application.[30] The development of suitable optical constructions with appropriate spectrum filters and externally (topically) applicable photosensitive substances became the basis of today’s applied PDD for bladder cancer, which was undertaken by German urologists in the late 1980s.[31] After the first hopeful results of decreased rates of residual tumors in reresections studies, comparing the recurrence rates of conventional TURBT and PDD were initiated. Some scientific groups demonstrated the superiority of PDD against conventional white-light TURBT, but for a long time, the application of 5-ALA remained off-label. Only the successful application of hexaminolevulinic acid led to the official approval of this agent in Europe and the USA.
Theory & Clinical Application of PDD
Effects of Heme Biosynthesis for PDD
In urology, 5-ALA was the first and most common clinically applicable active agent for fluorescence diagnosis – although it is not government approved. The advantage of this natural component of heme biosynthesis against other substances was the possibility of local administration, preventing side effects that had previously hindered the use of other photosensitizing substances.[30] 5-ALA is produced in the mitochondria, from glycine and succcinyl-CoA by the enzyme aminolevulinic acid synthase. Through several steps of synthesis, it turns into coproporphyrinogen III and protoporphyrinogen IV, and finally becomes protoporphyrin IX. Ferrochelatase causes the formation of heme through the insertion of iron, a component of the red blood pigment.[32]
When 5-ALA is administered topically, protoporphyrin IX is formed increasingly in (pre)malignant cells, whereas in healthy, normal cells, such accumulation is prevented by the inhibiting feedback mechanism. Only local topical application results in effects in the urothelium; orally or intravenous administration will not lead to fluorescence. Every substance emits spontaneous energy that can be made visible in special spectrums of light – dependent on the respective substance.[32] The reasons for the effect of 5-ALA causing fluorescence in malignant, but for example also in inflammatory or regenerating tissues, are considered to be the passive (cellular barrier disorders) and active (change in activity of carrier proteins) increase of 5-ALA concentration, leading to overexpression of protoporphyrin IX. The absorbance maximum of protoporphyrin IX lies in the wavelength area of blue light.[32] Under blue light at wavelength 345–440 nm, the difference in protoporphyrin IX accumulation between healthy and pathologically altered tissue appears as a red fluorescence.
After approval of hexaminolevulinic acid in 2009, Hexvix® (GE Healthcare, USA) replaced 5-ALA as the standard agent for PDD. The main advantage of hexyl-derivative esters (HALs) comes from their chemical construction, which improves the penetration of the lipophile cellular layer compared with 5-ALA.[33] This also leads to a reduced duration and required dose.[34] Accumulation of protoporphyrin IX is achieved not only more rapidly by HAL, but even two- to four-fold more intense although using a much smaller concentration of the agent compared with 5-ALA.[35] Other substances, for example hypericin, a hydroxylated phenanthroperylenequinone derived from plants such as Hypericum perforatum, only reached scientific interest and are under no further clinical evaluation.[34,35]
Performance of PDD in Routineous Transurethral Resection of Bladder Tumor, Reresection & Aftercare
The performance of TURBT with PDD is not substantially different from a TURBT under conventional white-light. It is rather a supplement, namely the preinterventional administration of the substance stimulating fluorescence. In the case of 5-ALA, 50 ml of 3% 5-ALA solution is filled in the bladder via a catheter 2–3 h prior to the planned transurethral resection. The liquid had to remain in the urinary bladder for approximately 2 h. The patient’s regular change of position ensures distribution over the entire surface.[36] The insertion of Hexvix approximately 1 h before surgery is enough to reach a good fluorescence during TURBT. In clinical practice, a urological nurse applicates the substance 1 h before TURBT by a short catheterization.
Photodynamic diagnosis is then always carried out in combination with a conventional cystoscopy, whereby the entire bladder, beginning at the urethral orifice around the bladder outlet over the floor of the bladder, the bladder walls and roof, is first examined under white-light with optics at variant angular degrees. Afterwards, one can easily switch to blue light (345–440 nm) and repeat the cystoscopy. Against a blue-shining background light, red-shining areas are suspicious of pathological lesions in the bladder mucosa. Their resection is the definite diagnostical step for suspected bladder carcinoma and, at the same time, the primary therapy of NMBC. The resected findings are not always malignant specimens so that, even under PDD a histopathological assessment is always needed. The relatively high share of false positivity is due to the fact that not only malignant cells, but also inflammatory and granulating cells, overexpress protoporphyrin IX.
Fluorescence diagnosis of bladder cancer is a well-tolerated examination method. While at earlier stages the systematic administration of protoporphyrin caused severe phototoxic side effects (especially platelet aggregation and vasoconstriction), today’s administration of the fluorescent substance into the bladder is a well-tolerated method without complications.[37] With TURBT under PDD, there are well-known possibilities of complication derived from the transurethral resection itself. These are mainly bleeding and urinary tract infections, as well as rare cases of injuries of the bladder wall. Regardless of the characteristics of the tumor disease, a single treatment of the bladder with a chemotherapeutic agent (mitomycin C) is recommended following TURBT. A second resection should be performed approximately 6 weeks after primary TURBT in cases of an incomplete initial resection and after a finding of high-grade tumor.[14] Repeated use of PDD in reresection is not recommended because of false-positive reactions after administration of Hexvix a few weeks after the first TURBT and BCG instillations for prophylaxis of recurrence and progression.[38]
However, for patients with low and medium risks, the focus is primarily on the danger of recurrence; progression to muscle-invasive tumors is a problem in high-risk patients that is not to be underestimated.[39] While in the first instance after surgery a single chemotherapeutic treatment is sufficient, high-risk patients need a maintenance immunotherapy with BCG over at least 1 year. The patient’s defense reaction, which has been triggered by the bacteria is to kill remaining tumor cells.[40] Regular aftercare cystoscopies are essential for the early detection of recurrences, which should be carried out on all patients approximately 3 months after the last positive TURBT. Owing to technical reasons, fluorescence diagnostics are not routinely used for aftercare cystoscopies. Since a cystoscopy under PDD makes sense only when ready for resection, patients would need to be anesthetized for each aftercare examination. Until now, PDD in aftercare has only experimental value and might be vital if regular PDD cystoscopy was considered better than established instillation treatments. There is ongoing investigation on this field.
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.
Based on clinically and economically convincing arguments, PDD with Hexvix became FDA approved and was included in diagnose-related group catalogues of several western countries. The importance of PDD might be even greater, when the main weakness of low specificity is handled better. Therefore, modifications of the fluorescent substance and of the endoscopic system are necessary. This also might facilitate the handling and, in this way, make the performance of PDD in the daily use more convenient for the user.
Especially by establishing new, more specific agents for PDD, the aspect of a combination with photodynamic therapy is conceivable. Here, for example, the evaluation and consideration of immunhistochemical markers known to be of prognostic value for NMBC might lead to an improvement of specificity. Together with more precise light sources in the future, this might even make postoperative instillation therapy redundant. Further prospective, randomized studies on the value of PDD for the aftercare of NMBC patients together with a necessary reduction of the investment costs for the light source and the agent purchase are possible forerunners to enable PDD, even in the outpatient setting.
