The Enlightenment of Bladder Cancer Treatment

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.

Table 1. Relevant publications on prospective randomized studies concerning residual tumor rate and recurrence-free survival rate for photodynamic diagnosis for urothelial bladder carcinoma.
Study (year)	PDD agent	Patients (n)	Residual tumor rate (%)		Median follow-up (months)	Recurrence-free survival rate (%)		Ref.
Study (year)	PDD agent	Patients (n)	WL TURBT	PDD TURBT	Median follow-up (months)	WL TURBT	PDD TURBT	Ref.
Riedl et al. (2001)	5-ALA	102	39.0	16.0	–	–	–	[52]
Kriegmair et al. (2002)	5-ALA	129	53.1	32.7	–	–	–	[53]
Filbeck et al. (2002)	5-ALA	191	25.2	4.5	21	65.9	89.6	[51]
Filbeck et al. (2003)	5-ALA	191	–	–	43	60.7	85.0	[63]
Daniltchenko et al. (2004)	5-ALA	115	41.0	16.0	12	35.4	53.2	[64]
Daniltchenko et al. (2005)	5-ALA	115	–	–	42	25.0	41.0	[55]
Babjuk et al. (2005)	5-ALA	122	37.0	8.0	24	28.0	40.0	[65]
Denzinger et al. (2007)	5-ALA	191	–	–	86	45.0	72.0	[56]
Denzinger et al. (2008)	5-ALA	46	41.0	12.0	90	52.0	80.0	[43]
Otto et al. (2009)	5-ALA	191	–	–	99	43.0	72.0	[57]
Burger et al. (2009)	5-ALA/HAL	416	33.0	15.0/9.0	24	67.0	80.0/82.0	[37]
Hermann et al. (2011)	HAL	145	–	–	12	52.7	69.5	[58]
Drãgoescu et al. (2011)	HAL	44	–	–	12	54.5	81.8	[59]

All study results showed p-values <0.05. 5ALA: 5-aminolevulinate acid; HAL: Hexaminolevulinate acid; PDD: Photodynamic diagnosis; TURBT: Transurethral resection of bladder tumor; WL: White-light.

Sidebar

Executive Summary

Urothelial Bladder Carcinoma

Bladder cancer is one of the most common neoplasms in western countries.
Standard treatment of nonmuscle-invasive bladder cancer is transurethral resection of the tumor (TURBT).

Transurethral Resection & PDD

The detection of flat lesions, such as carcinoma in situ , is demanding.
Since the 1990s, photodynamic diagnosis (PDD) has been an upcoming technique to improve detection of bladder tumors.

Theory & Clinical Application of PDD

Accumulation of protoporphyrin IX in tumor cells after instillation of the photodynamic substance in the bladder before TURBT leads to fluorescence in the blue-light wavelength.
Before US FDA approval of hexaminolevulinic acid, the substance 5-aminolevulinic acid (5-ALA) was used for PDD.

Indication & Results of PDD for Bladder Carcinoma

Despite low specificity due to protoporphyrin IX overexpression not only in malignant, but also in inflammatory cells, PDD reduces residual tumor rates after TURBT.
Decrease of recurrence rates, demonstrated in several studies, leads not only to a significant improvement of patients' quality of life, but also seems to have relevant reimbursment opportunities for the health system.

Limitations & Future Perspectives of PDD

Further prospective, randomized studies on the topic should particularly improve specificity and application of PDD in aftercare outpatient setting.

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