Holmium YAG Photocoagulation: Safe and Economical Alternative to Transurethral Resection in Small Nonmuscle-Invasive Bladder Tumors

Introduction

Approximately 75% of patients with bladder cancer present it as a superficial tumor confined to the mucosa (stage Ta, carcinoma in situ [CIS]) or submucosa (T1) that is characterized by recurrences in up to 75% of those cases. Between 5% and 10% of these recurrences will be less than 1 cm in size. ¹ This, together with the low cancer-specific mortality rate it has when compared with the T2-4 stages, makes it one of the most prevalent diseases of urology. The costs associated with its treatment and follow-up represent a real challenge for the National Health Systems. ²

The standard treatment for tumor recurrence is transurethral resection (TUR), but it is a technique that is not without complications ^3,4 and is aggravated by the fact that the population is ageing. Therefore, the search for less invasive and more economic alternatives is considered reasonable, especially for the treatment of those recurrences of small size that do not risk survival or, in those patients for whom the intervention would suppose, because of age or comorbidities, a high surgical risk.

Active vigilance is considered a therapeutic option for patients with important comorbidities, in treatment with anticoagulants and/or with tumors of less than 5 mm. ^5,6 However, the development of new technologies, in general, and of lasers in particular, has enabled the development of outpatient techniques for the treatment of these small tumor recurrences with acceptable safety and efficacy. ⁷

The Ho:YAG laser may have been one of the most commonly used, due in part to its low penetration that gives it greater safety, ^{8 –12} especially for patients with high surgical risk whose bladders are usually of low capacity or ischemic.

Our article describes our experience in the treatment of bladder tumor recurrences using a Holmium-YAG laser. It is a prospective, observational, descriptive study with one of the longest series so far reported. We carried out 139 procedures. Recurrence rates and tumor progression, degree of safety, and patient satisfaction are evaluated as well as the economic repercussions of this technique in our center.

Materials and Methods

We conducted a descriptive, prospective pilot study from February 2013 to 2016, which included 109 patients diagnosed with small recurrences of bladder urothelial cancer.

As a first step, a meeting was held between members of the Urology Service and a working group was appointed. At the meeting, the topic was discussed and an analysis of the clinical guidelines was made and a study protocol was designed and approved by the head of the service.

Patients were classified by previous transurethral resections based on the risk calculation of the European Organization for Research and Treatment of Cancer (EORTC).

Inclusion criteria were as follows: patients with low risk, intermediate risk of progression or recurrence, and high-risk patients of progression or recurrence but with a high surgical risk (ASA 4), with lesions less than or equal to 1.5 cm and in number less than or equal to 5 diagnosed by cystoscopy. Exclusion criteria were those patients with a history of CIS, previous positive urine cytology, patients with high tumor risk and ASA 1–3, and those patients who did not wish to participate in the study.

Patients were advised of the procedure and gave their subsequent informed consent.

A coagulation control analysis was carried out and patients were instructed to withdraw anticoagulants a few days beforehand, although 100 mg acetylsalicylic acid was allowed to continue.

Patients were treated on an outpatient basis in our screening room. The screening room is an adapted operating theatre, where urodynamics, transrectal biopsies, endovesical treatments, and cystoscopies are performed, among other techniques, and it is also equipped for consultations.

On the day of the test, patients were given a prophylactic antibiotic (gentamicin 240 mg i.m. or ceftriaxone 1 g i.m.). After cleaning of the genitals with povidone iodine, intraurethral anesthetic gel was applied with 2% lidocaine. A cystoscopy was performed with a flexible cystoscope 17 CH and 2% vials of lidocaine 5% per liter of saline were added to the irrigation serum. In cystoscopy, the entire bladder is checked to confirm lesions and barbotage cytology and a biopsy of cold-pinched lesions are collected. For photocoagulation, a Holmium:YAG fiber laser of 365 μm in diameter is used through the flexible cystoscopy working channel with an energy of 0.5–1 J/pulse and a frequency of 6–10 Hz. The base and surrounding healthy tissue are coagulated by keeping the fiber about 2 mm apart from the surface until it acquires the typical off-white discoloration that is characteristic of protein denaturalization and coagulation. The time taken for complete intervention (the patient going into and out of the room) and the time taken for vaporization, as well as any incidences that occurred during the technique were recorded. At the end of the procedure, the patients were given a survey consisting of a visual analogue scale (VAS) to score from 1 to 10 assessing the level of comfort experienced, and a urinary symptoms satisfaction questionnaire (USSQ) to fill on any complications, degree of satisfaction of the patient, and their preferences in case of a new recurrence. A urine culture flap was also attached for use 1 week after the procedure and a cystoscopy was scheduled for control at 3 months.

Patients who, on the day of the test, did not meet the inclusion criteria for increased tumor burden in the cystoscopy before fulguration, or those who were not able to undergo the technique due to complications or difficulty of access, were rescheduled for a few weeks later for an TUR in the operating room.

On the day of the control cystoscopy at 3 months, we collected the complications and satisfaction questionnaires. Patients with positive or suspect lavage cytologies were referred for imaging techniques to control the upper urinary tract.

If patients presented recurrences at 3 months, the number and location were recorded. Low-risk or intermediate-risk patients with recurrence at the same site were scheduled for new photocoagulation. Intermediate-risk patients with recurrence at a different site, with increased tumor burden, technical access difficulties, or high-risk patients were scheduled for TUR in the operating theatre.

Patients who did not present recurrences were scheduled 3 months later for a new cystoscopic review. In that new review, if they presented recurrences, they were programmed for photocoagulation or TUR. If the test was negative, it was included in the follow-up protocol of bladder tumors in our service, adjusted to its level of risk.

To compare costs, we used data from Decreto Legislativo 1/2005, dated February 25, of the Regional Government Council, TR LEY DE TASAS (EJERCICIO 2016). This law specifies the costs assigned to carry out a cystoscopy, outpatient procedures by fiber laser, and the cost of a conventional bladder TUR with 24-hour patient hospitalization without complications.

Data were analyzed using SPSS version 19 for Windows. In data analysis, the Kolmorogov–Smirnov Test was used to demonstrate the normality of the continuous variables. Subsequently, the continuous variables were analyzed using the Chi-square test and for the analysis of dichotomous quantitative–qualitative variables, Student's t-test was used for independent samples.

Results

From February 2013 to 2016, 139 procedures were carried out, of which 130 were completed. Of the nine losses, eight were reprogrammed for TUR because of a high tumor burden or a difficult access site, and the remaining loss occurred when the procedure was interrupted by an anxiety crisis and was rescheduled for TUR under anesthesia.

In the 130 completed procedures, the distribution of patients according to their risk of recurrence and progression was: 49 low risk (37.7%), 64 intermediate risk (49.2%), and 17 high risk (13.1%). Two hundred forty-six tumors were photocoagulated in total with a median of 1 tumor (1–5 tumors) and a mean size of 4 mm (2–15 mm).

Further details are shown in Table 1.

In the cystoscopic review at 3 months, 22 recurrences (16.92%) were detected in 130 photocoagulations, 14 of which were in the same location. Note that 15 of the 22 recurrences occurred during the first 75 procedures. In the cystoscopic review at 6 months, there were only 4 recurrences (3.7%) in 108 remaining procedures of which 3 were in the same location. In total, there were 26 cases of recurrence (20%) in the first 6 months, distributed by risk groups as follows: 23.1% (6/26) in the low-risk group, 69.2% (18/26) in the intermediate-risk group, and 7.7% (2/26) in the high-risk group.

Two patients (1.5%) presented intraoperative complications in the form of monosymptomatic hematuria, which made the technique difficult but did not interrupt the procedure and did not require therapeutic maneuvers. There were no other intraoperative complications. No patient required catheterization or subsequent admission. It was possible to perform the control urine culturing in 89.1% of patients, asymptomatic bacteriuria being positive for 9.3%.

Regarding the pathological anatomy of the samples, this could not be carried out in six procedures (4.6%) due to difficulty of access with the foreign body clamp. It was not conclusive due to an insufficient sample in six biopsies (4.6%). Of the others, 82 biopsies were positive, of which 77 (59.2%) were low-grade tumors and 5 (3.8%) were high grade. Note that there was no histological progression, and all recurrences of high histological grade were from patients who had previously been classified as high risk. Tumor recurrence was not observed in any of the patients with negative pathological anatomy.

Cytology was positive in 6.2% (8 cases) and inconclusive or inadequate in 7.6% (10 cases). All cases with positive cytology had a positive biopsy for tumor. Patients with a positive cytology corresponded in six of the eight cases to the intermediate or high tumor risk groups, and the eight patients presented negative imaging for upper urinary tract cancer.

A significant statistical relationship was found between the intermediate risk group and recurrence. However, this result should be treated with caution, since the intermediate-risk group is where most tumors were found, so it may be that the sample from the other groups is not large enough to show it.

The number of tumors found was statistically related to the presence of recurrences. However, they are not related to tumor size, photocoagulation time, or consultation time. There is no statistical relationship to age, or to the result of the pathological anatomy.

On the other hand, the number or size of tumors does not appear to relate to the histological result or the positive cytology result, but age is related to complications and the presence of asymptomatic bacteriuria.

Ninety-four patients answered the EVA questionnaire, the USSQ, and the surgical technique preference in case of new recurrence. A value equal to or less than 4 was reported by 94.7% of them in the VAS after the procedure (0–8) and 100% of the patients answered that if they had to undergo a new intervention they would prefer laser photocoagulation.

Further details are shown in Table 2.

In the USSQ, only 23% indicated the presence of dysuria and/or increased urinary frequency at home that lasted between 48 and 72 hours. There were no patients with hematuria of more than 24 hours and there was no complication of more than 72 hours. No patient required medical treatment because of complications, relieving the discomfort spontaneously.

For the calculation of costs, according to LEY DE TASAS del Gobierno Autonómico 2016: a 24-hour patient admission for carrying out an uncomplicated transurethral procedure is currently set at €2740.00. Carrying out the procedure in the Surgery Unit without admission is set at €978.46. The cost of a photocoagulation as an outpatient procedure is given as €732.91.

The Holmium laser unit would be the same as using the lithotripsy unit and, therefore, does not imply any extra expense.

In this way, the treatment of small bladder tumor recurrences with Ho:YAG laser results in a saving of €2007.09 per procedure. In our center, this would be a saving of €260,921.70 over 3 years. On top of this saving, when procedures are carried out in our screening room it will allow operating theatres to be available for other operations.

Discussion

TUR is the first choice treatment of superficial bladder tumors, but it is a surgical technique that requires such means as an operating room, participation of the anesthesia service, and hospitalization of the patient. In the 1990s, new techniques began for the treatment of superficial bladder tumors that were cheaper, less aggressive, and that offered guarantees of oncology control. ^1,10,13 The aim was to replace bladder TUR as a treatment for those small superficial bladder tumors for which it was considered an excessively aggressive technique, because of the characteristics of both the tumor and the patient. Reducing costs was also a benefit, since it is a disease that by its nature will require multiple interventions. ^{14 –16}

One of the first techniques developed was ambulatory cystodiathermy. However, in some series, there were high rates of recurrence and it was poorly tolerated with painful procedures registering up to 12%. ^1,17,18

The first reference to the use of laser for the treatment of superficial bladder tumors dates from the 1970s in Germany by Staehler and colleagues ¹⁹ and was approved for use in the USA in 1984. ⁸ Since then, with the development of technology, it has become a booming technique using various types of lasers and for the treatment of various pathologies. ^20,21

One of the main advantages of laser is that, by not transmitting electricity through the body, there is no nerve stimulation and the patient is in less discomfort. It also has better coagulation capacity. ^2,8

The neodymium:YAG laser was the first to be used with reasonable success, but it had to be abandoned when there were complications such as severe intestinal perforation. ^10,22

Photocoagulation of tumors with the Ho:YAG laser is the technology that has been studied the most. The Ho:YAG has a wavelength of 2100 nm, which gives it a special affinity for blood and water. The temperature required to produce irreversible changes in tissues due to denaturation of the proteins is 60–100°C, and vaporization occurs at temperatures above 100°C. This temperature is difficult to reach in an environment such as the bladder, being surrounded by fluids, which defines the Ho:YAG laser at a penetration depth of 0.5–1.0 mm, greatly limiting the chances of severe complications. ^8,9,21,22

Bladder TUR, despite being a widely used surgical technique worldwide, is not free of complications, which can be aggravated by the use of an anesthetic, elderly population, or on those with comorbidities. ^{14 –16}

Many reports cite the photocoagulation of bladder tumors with the Ho:YAG laser as a technique with few complications. ^10,23,24 This has made it an option to consider for patients of advanced age or with high surgical risk. ^9,22,25

In our series, there were no major intraoperative complications, just two episodes of hematuria, which did not require any treatment. In the postoperative period, only 23% of minor discomforts were reported. None of the significant bacteriuria that was detected in the postoperative urine cultures evolved into urinary infection and did not require antibiotic treatment. These results took into account the elderly population and those at risk of ASA IV and confirm the safety of the procedure.

The risk of recurrence, according to the EORTC risk calculator for superficial tumors of less than 3 cm, ranges from 15% to 65% per year, depending on the characteristics of the tumor. ²³ Published reports vary, registering values between 22% and 73% of tumor recurrences at 6 months with conservative treatments. ²¹ However, there are studies that have found no differences in the risk of recurrence between TUR treatment and Ho:YAG laser photocoagulation. ²⁴ Additionally, there are bodies of data that show a lower number of tumor recurrences in those patients treated with laser Ho:YAG. ^21,26,27 This evidence has led to the use of laser technology in the treatment of invasive bladder tumors, with variable results. ^11,12

In our series, we recorded a total recurrence rate at 6 months of 20% for all types of tumors, and the rate is about 12% in low-risk tumors. These figures are in line with what is reported, which fall within acceptable oncology control levels.

Because of its characteristics, the superficial bladder tumor is one of the neoplastic entities that will incur the most expense in its treatment throughout the life of a patient. ²⁸ It involves a large number of procedures that, therefore, need to be easily reproducible and incur the lowest possible cost.

Ho:YAG laser photocoagulation is a technique that does not require a lot of training, since most urologists are familiar with the use of lasers and the flexible cystoscope. However, it does require a period of adaptation that might be reflected in a greater number of recurrences after the initial procedures. ²⁹ There seem to be evidence for this in our study, when 15 of the 22 recurrences in the first 3 months were registered during the first 75 procedures.

One of the shortcomings of this technique is the lack of biopsies that are available for histological study and determination of muscle integrity. ^2,23,24 For our study, we performed a cold-clamp biopsy before photocoagulation to determine if there was progression at the histological level. We did not consider the lack of muscular biopsy especially relevant, since most of these tumors were unlikely to progress and invade the muscle. Also, patients at high risk of progression were given this technique because they were in such a fragile state that they were not candidates for any other type of surgery. There was no progression at the histological level, demonstrating acceptable cancer control.

There have been several studies on the cost effectiveness of Ho:YAG laser photocoagulation treatment in countries with different health systems from ours, which prevents us from comparing their costs. ^22,30 In our series, we have used the stipulated values laid down by Law established by our Regional Government. All the procedures are specified and evaluated economically in a global way, including the cost of materials and personnel. Photocoagulation as a procedure represents a saving by intervention of €2007.09 compared with conventional TUR without complications.

Part of the cost reduction of this technique is the lack of need for anesthetic, in addition to reducing its associated risks. However, that does not imply a loss of comfort on the part of the patient, as the results of our satisfaction survey and the EVA pain questionnaire will testify. In fact, when asked which technique they would prefer if they had to undergo a new intervention, all patients answered laser photocoagulation as the first option before a new bladder TUR.

Conclusions

Although this study does not provide long-term results, it suggests that the treatment of small recurrences of bladder tumor by photocoagulation with Ho:YAG laser is a well-tolerated, cost-effective technique that offers good cancer control and requires very little learning curve to ensure satisfactory results. We have noted few complications for fragile elderly patients or those with multiple comorbidities who might not tolerate anesthetic or other more invasive interventions. Longer-term randomized trials are required to confirm this.