- Email: [email protected]
Outpatient Holmium laser fulguration: A safe procedure for treatment of recurrence of nonmuscle invasive bladder cancer
Actas Urol Esp. 2018;42(5):309---315
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Outpatient Holmium laser fulguration: A safe procedure for treatment of recurrence of nonmuscle invasive bladder cancer夽 Á. Rivero Guerra ∗ , T. Fernández Aparicio, I. Barceló Bayonas, A. Pardo Martínez, noz Guillermo, D. Jiménez Peralta, C. Carrillo George, B.N. Pietricica, V. Mu˜ E. Izquierdo Morejón, A. Rosino Sánchez, A. Romero Hoyuela, G. Hita Villaplana Servicio de Urología, Hospital General Universitario J. M. Morales Meseguer, Murcia, Spain Received 3 October 2017; accepted 13 December 2017 Available online 27 April 2018
KEYWORDS Nonmuscle invasive bladder cancer; Outpatient fulguration; Holmium laser
Abstract Background and objective: Nonmuscle invasive bladder cancer has a high recurrence rate and a low progression rate. The aim of this study was to assess the effectiveness, safety and feasibility of Holmium laser fulguration in an outpatient regimen for selected tumors. Material and method: A prospective, longitudinal cohort study was conducted between January 2009 and December 2016. Seventy-nine Holmium laser fulguration procedures with subsequent instillation of mitomycin C were performed in an outpatient regimen on 59 patients with a history of low-risk bladder cancer and recurrence of small papillary tumors. We performed a descriptive data analysis and analyzed the relapse-free time using Kaplan---Meier curves. Results: All procedures were completed in one day, and only one patient required subsequent hospitalization due to haematuria. Some 87.2% of the patients presented pain with a visual analog score ≤3. Recurrence occurred after 49.4% of the procedures (27.3% at 12 months). The median follow-up time was 17 months (range, 2---65). The onset of recurrence was significantly earlier after the second fulguration than after the first (median, 10 months vs. 56 months). Conclusions: Holmium laser fulguration and subsequent mitomycin C instillation in an outpatient regimen is a safe and feasible alternative to transurethral resection of bladder tumors in selected patients. Transurethral resection of the bladder tumor is recommended for patients with recurrence after fulguration, given the possibly higher risk of progression in these patients. © 2018 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Rivero Guerra Á, Fernández Aparicio T, Barceló Bayonas I, Pardo Martínez A, Mu˜ noz Guillermo V, Jiménez Peralta D, et al. Fulguración ambulatoria con láser Holmium: Un procedimiento seguro para el tratamiento de la recidiva del carcinoma vesical no músculo infiltrante. Actas Urol Esp. 2018;42:309---315. ∗ Corresponding author. E-mail address: [email protected] (Á. Rivero Guerra).
2173-5786/© 2018 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
310
PALABRAS CLAVE Cáncer vesical no músculo-invasivo; Fulguración ambulatoria; Láser Holmium
Á. Rivero Guerra et al. Fulguración ambulatoria con láser Holmium: Un procedimiento seguro para el tratamiento de la recidiva del carcinoma vesical no músculo infiltrante Resumen Introducción y objetivo: Los tumores vesicales no musculo-invasivos presentan una elevada tasa de recurrencias y una baja tasa de progresión. El objetivo del estudio es evaluar la efectividad, seguridad y factibilidad de la fulguración con láser Holmium en régimen ambulatorio en tumores seleccionados. Material y método: Estudio prospectivo, longitudinal, de cohortes (enero de 2009 hasta diciembre de 2016). Se realizaron 79 procedimientos de fulguración con láser Holmium + instilación posterior de MMC en régimen ambulatorio en 59 pacientes con historia de neoplasia vesical de bajo riesgo y recidivas papilares de peque˜ no tama˜ no. Se realiza un análisis descriptivo de los datos y se analiza el tiempo libre de recidiva mediante curvas de Kaplan-Meier. Resultados: Todos los procedimientos se completaron en el día y sólo un paciente precisó ingreso posterior por hematuria. El 87.2% de los pacientes presentó dolor con EVA ≤ 3. Se objetivó recidiva tras el 49.4% de los procedimientos (27.3% a los 12 meses). La mediana de seguimiento fue de 17 meses (rango 2-65). La aparición de recidiva fue significativamente más precoz tras la segunda fulguración que tras la primera (mediana: 10 meses vs 56 meses). Conclusiones: La fulguración con láser Holmium + instilación posterior de MMC en régimen ambulatorio es una alternativa segura y factible a la RTUv en pacientes con tumores seleccionados. Probablemente sea recomendable realizar una RTUv en los pacientes con recidiva tras fulguración, dado que posiblemente el riesgo de progresión en estos pacientes es superior. © 2018 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Bladder cancer is the fourth tumor in frequency in the world population. In Europe, the age-standardized incidence (per 100,000 h/year) is 27 for men and 6 for women.1 In our country, the incidence adjusted by age to the European population is 20.08; 84% of these cases occur in males, 82% of them presenting an age equal to or greater than 60 years.2 Although 75% of these lesions appear as non-muscleinvasive tumors, they present an estimated risk of recurrence between 31% and 78% and progression of up to 45%.3 However, in lesions with a low malignancy potential, the risk of progression is lower than 1%. The major predictors of recurrence and progression are known: stage, size, number of lesions, presence of associated CIS, and previous recurrences.4 The biology of these injuries requires, therefore, a close follow-up. The high recurrence rate and the low rate of progression result in the need for multiple procedures throughout the follow-up of these patients, whether traditional transurethral resection (BTUR), fulguration by electrical energy,5 or laser ablation.6 On the other hand, many of these patients have advanced age and multiple comorbidities, which can lead to an increased risk of mortality and complications derived from multiple admissions and interventions. Although the health expenditure derived from the treatment of the primary tumor and the possible recurrences have not been well analyzed, a cohort study in the USA estimated in 2006 the average of total cost per patient in $65,000: 60% of the expenses depended on the surveillance and treatment of recurrences and 30% derived from associated complications.7
The objective of this study is to evaluate the efficacy, safety, and feasibility of Holmium laser fulguration, in an outpatient setting, of selected tumors in patients with a history of low-risk bladder tumors.
Material and methods Prospective, longitudinal, cohort study developed from January 2009 to December 2016. The patients were included in the study following the scheme proposed by Donat S.M in 2004,8 modified (Fig. 1). In this way, the inclusion criteria were the following: • Prior papillary neoformation of low grade and stage (TaG12). • Size equal to or smaller than 10 mm. • Number of implants equal to or lower than 5. • Negative cytologies. • Low-grade recurrence in the opinion of the endoscopist. • No demonstrated allergy to lidocaine. • Acceptance of the procedure and signing of the informed consent. The process was designed prior to its implementation, establishing the ambulatory circuit and the specific tasks of clerks, assistants, nursing, and physician, as well as the indicators for their evaluation, as shown in Fig. 2. Prerequisites and instructions for patients: • Fasting from the previous night. • Ingestion of their usual medication. Change oral anticoagulant guidelines as in the preparation for any intervention.
Outpatient Holmium laser fulguration
311 No relapse
- Citologies
Initial diagnosis (TUR): low malignancy potencial
Surveillance protocol
Outpatient fulguration
Relapse: - <10 mm - <6 implants - Papillary aspect
+Citologies
Tradicional TUR
Relapse rest of circumstances
Figure 1
Scheme of bladder tumor management with low malignancy potential. Adapted from Donat S.M.
UROLOGY DEPARTMENT
BLUE AREA (outpatient in ward)
ARCHIVE
Surgical proposal for outpatient fulguration
Information to patient and relatives
Performing fulguration
Drafting the report
Physician Activity programming
Mechanization
Clerk
Patient telephone citation
Citation in outpatient consultations Sending the work order
Preparation of histories
Sending to BLUE AREA
Patient reception
Assistant
Patient preparation
Checking matches Reporting incidente
Nursing
DOES IT MATCH?
MMC instillation
No Yes Material preparation
Figure 2
Flow chart of the ‘bladder fulguration’ process.
• Antibiotic prophylaxis (500 mg cefuroxime if not allergies). • Premedication 2 h before: • Nolotil 2 tablets (if not allergies). • 5 mg diazepam.
• Instilación of 100 ml solution of saline with 2 ampoules of 2% lidocaine (400 mg/100 ml). Remove probe and wait 10 min.
The surgical procedure was performed by a single surgeon, following the following guideline: Anesthetic procedure: • Placement of a dose of lidocaine gel, which is repeated 5 min after the initial one.
• Patient in supine position. • Insertion of flexible cystoscope. Performing exhaustive cystoscopy.
312
Á. Rivero Guerra et al.
• Insertion of 365 nm laser fiber and fulguration of the lesions, with energy of 0.5---1 J and frequency between 5 and 10 pulses (maximum power 10 w), from the periphery to the base. • Ensure hemostasis. • Probing, complete bladder emptying and instillation of 40 mg of MMC in 50 ml of physiological saline immediately after completing the procedure; it is maintained at least 60 min with changes of position in the patient’s bed every 15 min. • Patient discharge at the end, after checking the absence of hematuria and spontaneous micturition. After fulguration, a first cystoscopy and urinary cytology of follow-up at 3 months is carried out; then, the usual pattern continues: half-yearly until two years and then annually.
1,0
Cumulative survival
0,8
0,6
0,4
0,2
0,0 ,00
20,00
40,00
60,00
Follow-up
Figure 3 Recurrence after performing ambulatory fulguration. Survival curve (months).
Statistical analysis The statistical analysis was carried out with SPSS v.23. A descriptive analysis of the data was performed and the recurrence-free time was analyzed using Kaplan Meier curves. We used the Log-Rank test to compare survival curves between different groups, with p < 0.05 as the cut-off point for statistical significance.
Results In the period of time between January 2009 and December 2016, a total of 85 procedures were performed in 65 patients, of which 79 procedures in 59 patients are valid for this study, with a median follow-up of 17 months (range 2---65). Patients not included in this study had a history of T1G1-G2 bladder neoplasms, papillary recurrences of very small surface appearance, and negative cytologies. The number of procedures is greater than that of patients because patients could be subjected to it more than once during the follow-up. The basic demographic characteristics of the patients included in the study and of the lesions treated are shown in Table 1. The pathological anatomy of the lesions in the previous TUR was: TaG1 47 patients (79.66%), TaG2 10 patients (16.94%), atypical cystitis 1 patient (1.69%), and focal hyperplasia 1 patient (1.69%). The median time from previous TUR to fulguration was 27 months (range 4---148). Regarding previous treatment with intravesical instillations: 23 patients (38.98%) had not received any type of treatment, 33 patients
Table 1
(55.93%) had received MMC instillations, and 2 patients (3.38%) had received instillations with BCG. All procedures were completed on the day and only one patient required subsequent admission due to hematuria. The treatment was well tolerated, with a median of pain according to the VAS scale of 1 and 87.2% of patients with pain according to the visual analog scale (VAS) of ≤3 (range 0---7). Relapse was observed after 49.4% of procedures; in 50% of the cases, recurrence occurred at 27 months (median follow-up) (Fig. 3). After the recurrence, it was necessary to perform BTUR in 13 patients (22.03%), of which only 3 (5.08% of the total of patients) presented progression (either of stage, grade, or both) although in no case was progression observed to a muscle-infiltrating bladder tumor. Two of these patients presented progression after a second fulguration. Of the 6 patients with a history of bladder neoplasm T1G1-2, only one patient had recurrence after fulguration, performing subsequent BTUR with CIS finding in the anatomopathological study. Significant differences in the time to recurrence were observed from the treatment of the first tumor (median 56 months) as opposed to time to recurrence from the treatment of a second tumor (median of 10 months) (LogRank test p < 0.0001) (Fig. 4). The median time to recurrence between the group of patients who were smokers was 25 months and 28 months for patients who were not. This difference was not statistically significant (LogRank test p = 0.389) (Fig. 5).
Age of the patients and elementary characteristics of the treated lesions.
Minimum Maximum Mean Standard deviation
Age (years)
Number of TUR
Number of lesions
Size of the lesion (mm)
45 86 66.29 10.631
1 6 1.59 .942
1 7 1.83 1.230
2 13 4.81 2.346
Outpatient Holmium laser fulguration
313 1,0
1,0
LogRank test p=0.389
LogRank test p<0.0001 Relapse after first tumor
0,8
Cumulative survival
Cumulative survival
0,8
0,6
0,4 Relapse after second tumor
0,6 Non-smoker
0,4 Smoker
0,2 0,2 0,0 ,00
20,00
40,00
60,00
Follow-up
0,0 0,0
20,00
40,00
60,00
Follow-up
Figure 4 Recurrence after fulguration of a first and a second tumor. Survival curve (months).
Discussion Although BTUR represents the standard treatment of NMIBT, during the last two decades, a search and implementation of alternatives in the management of recurrences of low-grade NMIBT has been carried out in order to reduce the number of surgical interventions that these patients undergo and, in this way, reduce the costs and morbidity derived from hospital admission and surgery. Among these alternatives to BTUR, we find laser fulguration, ‘en bloc’ ® laser resection, ‘en bloc’ resection with Hybrid Knife ,9 fulguration with electrical energy, and active surveillance. Fulguration under local anesthesia is an alternative to the BTUR recognized in the clinical practice guidelines of the European Association of Urology (EAU)10 and the American Association of Urology (AUA)11 in patients with a history of low-risk tumors and papillary recurrences of small size. In our experience, Holmium laser fulguration under local anesthesia and immediately subsequent instillation of MMC on an outpatient basis has proved to be a feasible alternative to BTUR in patients with selected tumors. As published in a pilot study12 and in line with other publications,13---15 in our center, the outpatient procedure and with the aforementioned local anesthesia protocol it was effective, well tolerated, and associated with a low risk of subsequent complications. Traditionally, the potential advantages of Holmiun laser fulguration versus BTUR in the most fragile patients (more advanced age, more comorbidities) from the point of view of diminishing the anesthetic, surgical risk, and complications associated with admission have been more relevant.13 However, in our study, we also decided to include young patients (mean age 66.2 years, range 45---86) and with fewer comorbidities since this group of patients will be subject, presumably, to a longer follow-up period and may benefit from the decrease in the number of conventional surgeries without increasing the risk of progression. From the oncological point of view, at 12 months, relapse was observed after 27.3% of the procedures, in contrast
Figure 5 Recurrence after fulguration in the group of smokers versus non-smokers. Survival curve (months).
to the results obtained by Wong, KA and collaborators,13 who present 65.1% and 46.9% in patients with conventional cystoscopy and with photodynamic diagnosis (PDD), respectively. This lower rate of recurrence in our study could be explained by the performance of a post-procedure MMC instillation and by the lower heterogeneity of our series in terms of previous histology, given that in the Wong series, KA includes patients with high-risk tumors. (T1G3, CIS) and muscle-invasive (T2G3) with small-sized recurrences in patients with a high surgical risk. Although in our series we did not use PDD since it is not available in our center, its use could possibly improve the detection of non-visible lesions with conventional cystoscopy and, therefore, decrease the risk of relapse after fulguration. This lower rate of recurrence in our study could be explained by the performance of a post-procedure MMC instillation and by the lower heterogeneity of our series in terms of previous histology, given that in the Wong series, KA includes patients with high-risk tumors (T1G3, CIS) and muscle-invasive (T2G3) with small-sized relapses in patients with a high surgical risk. Although in our series we did not use PDD since it is not available in our center, its use could possibly improve the detection of non-visible lesions with conventional cystoscopy and, therefore, decrease the risk of relapse after fulguration. The results of Hossain MZ and collaborators16 draw attention, who present a series of 30 cases of recurrent (n = 18) and primary (n = 12) tumors treated under spinal anesthesia by ablation (tumors <1 cm) and resection (tumors 1---4 cm) with Holmium laser, without the appearance of any recurrence in the first 6---12 months of follow-up. More similar to our results are those of de PlanellesGómez et al.17 in their series of 130 Holmium laser fulguration procedures under local anesthesia, in which patients with a history of low, intermediate, and high-risk tumors are included, with 20% of relapses in the first 6 months of follow-up. The decrease in the time free of recurrence in patients after the second fulguration compared to patients after the
314 first fulguration is remarkable (median: 10 vs. 56 months). Probably, it would be convenient to perform a BTUR in patients in whom relapse is observed after fulguration since this group of patients is the one with the highest risk of progression. Some authors18,19 have proposed active surveillance as an alternative to immediate BTUR after the diagnosis of relapse; that is, postpone the BTUR until the patient presents criteria to exit the protocol (increase in the number of lesions or growth of these, appearance of positive cytologies or symptoms). In the most extensive active surveillance study published so far, Hernández and colleagues present a series of 252 periods of active surveillance in 186 patients between 1999 and 2014, with a median follow-up of 6 years. Although the median time that the BTUR could be postponed was 13.4 months and 22 patients (8.7%) remained in active surveillance for more than 3 years, 4 patients had progression to T2G3 (2 of them with involvement of lymph nodes). Although laser fulguration prevents the collection of histological material and we cannot assure the absence of progression in the majority of our patients due to the absence of anatomopathological analysis in the vast majority of cases, the appearance of the lesion in cystoscopy can be informative enough to identify recurrent, non-invasive, and low-grade papillary tumors.20 From the economic point of view, Wong13 and collaborators present in their series a cost-effectiveness analysis with which they conclude that, for the £30,000/QALY threshold established by the National Institute for Health and Care Excellence (NICE), outpatient fulguration is a cost-effective procedure with a probability of 81.9%. Although a formal analysis of the procedure costs has not been carried out in the present study, we can estimate the number of operating room and hospital stay days avoided in our center. Given that the average postoperative stay after BTUR in our Department is 4 days and that usually 4 patients can be operated per day of the operating room, we can estimate that thanks to the treatment by outpatient fulguration, between 260 and 340 days of hospital stay and between 16 and 21 days of surgery were avoided, approximately. These data are illustrative and may vary in centers with different surgical activity and different postoperative average stay.
Conclusions Fulguration with Holmium laser under local anesthesia and subsequent instillation of MMC in outpatient regimen is a safe and feasible alternative to BTUR in patients with small papillary recurrences and a history of low risk NMIBT. It is probably advisable to perform a BTUR in patients with relapse after fulguration, since the risk of progression in this group of patients is possibly higher.
Conflict of interest The authors declare that they have no conflict of interest.
Á. Rivero Guerra et al.
References 1. Ferlay J, Bray F, Forman D, Soerjomataram I, Dikshit R, Eser S, et al. GLOBOCAN 2008 v1.2, cancer incidence and mortality worldwide: IARC cancer base no. 10. Lyon, France: International Agency for Research on Cancer; 2010. 2. Mi˜ nana B, Cozar JM, Palou J, Unda Urzaiz M, Medina-Lopez RA, SubiraRios J, et al. Bladder cancer in Spain 2011: population based study. J Urol. 2014;191:323---8. 3. Alfred Witjes J, Lebret T, Comperat EM, Cowan NC, De Santis M, Bruins HM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur Urol. 2017;71:462---75. 4. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49: 466---75 [discussion 75---7]. 5. Herr HW, Legacy of E. Beer: fulguration ofpapillary bladder tumors. J Urol. 2005;173:1087---9. 6. Kramer MW, Rassweiler JJ, Klein J, Martov A, Baykov N, Lusuardi L, et al. En bloc resection of urothelium carcinoma of the bladder (EBRUC): a European multicenter study to compare safety, efficacy, and outcome of laser and electrical en bloc transurethral resection of bladder tumor. World J Urol. 2015;33:1937---43. 7. Avritscher EB, Cooksley CD, Grossman HB, Sabichi AL, Hamblin L, Dinney CP, et al. Clinical model of lifetime cost of treating bladder cancer and associated complications. Urology. 2006;68:549---53. 8. Donat SM, North A, Dalbagni G, Herr HW. Efficacy of office fulguration for recurrent low grade papillary bladder tumors less than 0.5 cm. J Urol. 2004;171 Pt 1:636---9. 9. Islas-García JJO, Campos-Salcedo JG, López-Benjume BI, Torres-Gómez JJ, Aguilar-Colmenero J, Martínez-Alonso IA, et al. Técnica quirúrgica de la resección transuretral de ® tumor vesical en bloque con HybridKnife . Actas Urol Esp. 2016;40:263---7. 10. Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol. 2017;71: 447---61. 11. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol. 2016;196: 1021---9. 12. Cano-García MC, Fernández-Aparicio T, Hidalgo-Agulló G, ReinaAlcaina L, Carrillo-George C, Rivero-Guerra A, et al. Fulguración con láser de la recidiva de tumores vesicales superficiales bajo anestesia local Dise˜ no de procesos. Rev Chil Cir. 2015;67: 292---8. 13. Wong KA, Zisengwe G, Athanasiou T, O’Brien T, Thomas K. Outpatient laser ablation of non-muscle-invasive bladder cancer: is it safe, tolerable and cost-effective? BJU Int. 2013;112: 561---7. 14. Soler-Martínez J, Vozmediano-Chicharro R, Morales-Jiménez P, Hernández-Alcaraz D, Vivas-Vargas E, Santos García-Vaquero I, et al. Holmium laser treatment for low grade, low stage. Noninvasive bladder cancer with local anesthesia and early instillation of Mitomycin C. J Urol. 2007;178:2337---9. 15. Morten J, Lund L, Biballe S. Holmium: YAG laser vaporization of recurrent papillary tumours of the bladder under local anaesthesia. BJU Int. 2004;94:322---5. 16. Hossain MZ, Khan SA, Salam MA, Hossain S, Islam R. Holmium YAG laser treatment of superficial bladder carcinoma. Mymensingh Med J. 2005;14:13---5.
Outpatient Holmium laser fulguration 17. Planelles-Gómez J, Olmos-Sánchez L, Cardosa-Benet JJ, Martínez-López E, Vidal-Moreno JF. Holmium YAG photocoagulation: safe and economical alternative to transurethral resection in small non muscle-invasive bladder tumors. J Endourol. 2017;31:674---8. 18. Hernández V, Llorente C, De la Pe˜ na E, Pérez-Fernández E, Guijarro A, Sola I. Long-term oncological outcomes of an active
315 surveillance program in recurrent low grade Ta bladder cancer. Urol Oncol. 2016;34, 165.e19---23. 19. Soloway MS, Bruck DS, Kim SS. Expectant management of small, recurrent, noninvasive papillary bladder tumors. J Urol. 2003;170:438---41. 20. Herr HW. Does cystoscopy correlate with the histology of recurrent papillary tumours of the bladder? BJU Int. 2001;88:683---5.
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Outpatient Holmium laser fulguration: A safe procedure for treatment of recurrence of nonmuscle invasive bladder cancer夽 Á. Rivero Guerra ∗ , T. Fernández Aparicio, I. Barceló Bayonas, A. Pardo Martínez, noz Guillermo, D. Jiménez Peralta, C. Carrillo George, B.N. Pietricica, V. Mu˜ E. Izquierdo Morejón, A. Rosino Sánchez, A. Romero Hoyuela, G. Hita Villaplana Servicio de Urología, Hospital General Universitario J. M. Morales Meseguer, Murcia, Spain Received 3 October 2017; accepted 13 December 2017 Available online 27 April 2018
KEYWORDS Nonmuscle invasive bladder cancer; Outpatient fulguration; Holmium laser
Abstract Background and objective: Nonmuscle invasive bladder cancer has a high recurrence rate and a low progression rate. The aim of this study was to assess the effectiveness, safety and feasibility of Holmium laser fulguration in an outpatient regimen for selected tumors. Material and method: A prospective, longitudinal cohort study was conducted between January 2009 and December 2016. Seventy-nine Holmium laser fulguration procedures with subsequent instillation of mitomycin C were performed in an outpatient regimen on 59 patients with a history of low-risk bladder cancer and recurrence of small papillary tumors. We performed a descriptive data analysis and analyzed the relapse-free time using Kaplan---Meier curves. Results: All procedures were completed in one day, and only one patient required subsequent hospitalization due to haematuria. Some 87.2% of the patients presented pain with a visual analog score ≤3. Recurrence occurred after 49.4% of the procedures (27.3% at 12 months). The median follow-up time was 17 months (range, 2---65). The onset of recurrence was significantly earlier after the second fulguration than after the first (median, 10 months vs. 56 months). Conclusions: Holmium laser fulguration and subsequent mitomycin C instillation in an outpatient regimen is a safe and feasible alternative to transurethral resection of bladder tumors in selected patients. Transurethral resection of the bladder tumor is recommended for patients with recurrence after fulguration, given the possibly higher risk of progression in these patients. © 2018 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
夽 Please cite this article as: Rivero Guerra Á, Fernández Aparicio T, Barceló Bayonas I, Pardo Martínez A, Mu˜ noz Guillermo V, Jiménez Peralta D, et al. Fulguración ambulatoria con láser Holmium: Un procedimiento seguro para el tratamiento de la recidiva del carcinoma vesical no músculo infiltrante. Actas Urol Esp. 2018;42:309---315. ∗ Corresponding author. E-mail address: [email protected] (Á. Rivero Guerra).
2173-5786/© 2018 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
310
PALABRAS CLAVE Cáncer vesical no músculo-invasivo; Fulguración ambulatoria; Láser Holmium
Á. Rivero Guerra et al. Fulguración ambulatoria con láser Holmium: Un procedimiento seguro para el tratamiento de la recidiva del carcinoma vesical no músculo infiltrante Resumen Introducción y objetivo: Los tumores vesicales no musculo-invasivos presentan una elevada tasa de recurrencias y una baja tasa de progresión. El objetivo del estudio es evaluar la efectividad, seguridad y factibilidad de la fulguración con láser Holmium en régimen ambulatorio en tumores seleccionados. Material y método: Estudio prospectivo, longitudinal, de cohortes (enero de 2009 hasta diciembre de 2016). Se realizaron 79 procedimientos de fulguración con láser Holmium + instilación posterior de MMC en régimen ambulatorio en 59 pacientes con historia de neoplasia vesical de bajo riesgo y recidivas papilares de peque˜ no tama˜ no. Se realiza un análisis descriptivo de los datos y se analiza el tiempo libre de recidiva mediante curvas de Kaplan-Meier. Resultados: Todos los procedimientos se completaron en el día y sólo un paciente precisó ingreso posterior por hematuria. El 87.2% de los pacientes presentó dolor con EVA ≤ 3. Se objetivó recidiva tras el 49.4% de los procedimientos (27.3% a los 12 meses). La mediana de seguimiento fue de 17 meses (rango 2-65). La aparición de recidiva fue significativamente más precoz tras la segunda fulguración que tras la primera (mediana: 10 meses vs 56 meses). Conclusiones: La fulguración con láser Holmium + instilación posterior de MMC en régimen ambulatorio es una alternativa segura y factible a la RTUv en pacientes con tumores seleccionados. Probablemente sea recomendable realizar una RTUv en los pacientes con recidiva tras fulguración, dado que posiblemente el riesgo de progresión en estos pacientes es superior. © 2018 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Bladder cancer is the fourth tumor in frequency in the world population. In Europe, the age-standardized incidence (per 100,000 h/year) is 27 for men and 6 for women.1 In our country, the incidence adjusted by age to the European population is 20.08; 84% of these cases occur in males, 82% of them presenting an age equal to or greater than 60 years.2 Although 75% of these lesions appear as non-muscleinvasive tumors, they present an estimated risk of recurrence between 31% and 78% and progression of up to 45%.3 However, in lesions with a low malignancy potential, the risk of progression is lower than 1%. The major predictors of recurrence and progression are known: stage, size, number of lesions, presence of associated CIS, and previous recurrences.4 The biology of these injuries requires, therefore, a close follow-up. The high recurrence rate and the low rate of progression result in the need for multiple procedures throughout the follow-up of these patients, whether traditional transurethral resection (BTUR), fulguration by electrical energy,5 or laser ablation.6 On the other hand, many of these patients have advanced age and multiple comorbidities, which can lead to an increased risk of mortality and complications derived from multiple admissions and interventions. Although the health expenditure derived from the treatment of the primary tumor and the possible recurrences have not been well analyzed, a cohort study in the USA estimated in 2006 the average of total cost per patient in $65,000: 60% of the expenses depended on the surveillance and treatment of recurrences and 30% derived from associated complications.7
The objective of this study is to evaluate the efficacy, safety, and feasibility of Holmium laser fulguration, in an outpatient setting, of selected tumors in patients with a history of low-risk bladder tumors.
Material and methods Prospective, longitudinal, cohort study developed from January 2009 to December 2016. The patients were included in the study following the scheme proposed by Donat S.M in 2004,8 modified (Fig. 1). In this way, the inclusion criteria were the following: • Prior papillary neoformation of low grade and stage (TaG12). • Size equal to or smaller than 10 mm. • Number of implants equal to or lower than 5. • Negative cytologies. • Low-grade recurrence in the opinion of the endoscopist. • No demonstrated allergy to lidocaine. • Acceptance of the procedure and signing of the informed consent. The process was designed prior to its implementation, establishing the ambulatory circuit and the specific tasks of clerks, assistants, nursing, and physician, as well as the indicators for their evaluation, as shown in Fig. 2. Prerequisites and instructions for patients: • Fasting from the previous night. • Ingestion of their usual medication. Change oral anticoagulant guidelines as in the preparation for any intervention.
Outpatient Holmium laser fulguration
311 No relapse
- Citologies
Initial diagnosis (TUR): low malignancy potencial
Surveillance protocol
Outpatient fulguration
Relapse: - <10 mm - <6 implants - Papillary aspect
+Citologies
Tradicional TUR
Relapse rest of circumstances
Figure 1
Scheme of bladder tumor management with low malignancy potential. Adapted from Donat S.M.
UROLOGY DEPARTMENT
BLUE AREA (outpatient in ward)
ARCHIVE
Surgical proposal for outpatient fulguration
Information to patient and relatives
Performing fulguration
Drafting the report
Physician Activity programming
Mechanization
Clerk
Patient telephone citation
Citation in outpatient consultations Sending the work order
Preparation of histories
Sending to BLUE AREA
Patient reception
Assistant
Patient preparation
Checking matches Reporting incidente
Nursing
DOES IT MATCH?
MMC instillation
No Yes Material preparation
Figure 2
Flow chart of the ‘bladder fulguration’ process.
• Antibiotic prophylaxis (500 mg cefuroxime if not allergies). • Premedication 2 h before: • Nolotil 2 tablets (if not allergies). • 5 mg diazepam.
• Instilación of 100 ml solution of saline with 2 ampoules of 2% lidocaine (400 mg/100 ml). Remove probe and wait 10 min.
The surgical procedure was performed by a single surgeon, following the following guideline: Anesthetic procedure: • Placement of a dose of lidocaine gel, which is repeated 5 min after the initial one.
• Patient in supine position. • Insertion of flexible cystoscope. Performing exhaustive cystoscopy.
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• Insertion of 365 nm laser fiber and fulguration of the lesions, with energy of 0.5---1 J and frequency between 5 and 10 pulses (maximum power 10 w), from the periphery to the base. • Ensure hemostasis. • Probing, complete bladder emptying and instillation of 40 mg of MMC in 50 ml of physiological saline immediately after completing the procedure; it is maintained at least 60 min with changes of position in the patient’s bed every 15 min. • Patient discharge at the end, after checking the absence of hematuria and spontaneous micturition. After fulguration, a first cystoscopy and urinary cytology of follow-up at 3 months is carried out; then, the usual pattern continues: half-yearly until two years and then annually.
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Cumulative survival
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Figure 3 Recurrence after performing ambulatory fulguration. Survival curve (months).
Statistical analysis The statistical analysis was carried out with SPSS v.23. A descriptive analysis of the data was performed and the recurrence-free time was analyzed using Kaplan Meier curves. We used the Log-Rank test to compare survival curves between different groups, with p < 0.05 as the cut-off point for statistical significance.
Results In the period of time between January 2009 and December 2016, a total of 85 procedures were performed in 65 patients, of which 79 procedures in 59 patients are valid for this study, with a median follow-up of 17 months (range 2---65). Patients not included in this study had a history of T1G1-G2 bladder neoplasms, papillary recurrences of very small surface appearance, and negative cytologies. The number of procedures is greater than that of patients because patients could be subjected to it more than once during the follow-up. The basic demographic characteristics of the patients included in the study and of the lesions treated are shown in Table 1. The pathological anatomy of the lesions in the previous TUR was: TaG1 47 patients (79.66%), TaG2 10 patients (16.94%), atypical cystitis 1 patient (1.69%), and focal hyperplasia 1 patient (1.69%). The median time from previous TUR to fulguration was 27 months (range 4---148). Regarding previous treatment with intravesical instillations: 23 patients (38.98%) had not received any type of treatment, 33 patients
Table 1
(55.93%) had received MMC instillations, and 2 patients (3.38%) had received instillations with BCG. All procedures were completed on the day and only one patient required subsequent admission due to hematuria. The treatment was well tolerated, with a median of pain according to the VAS scale of 1 and 87.2% of patients with pain according to the visual analog scale (VAS) of ≤3 (range 0---7). Relapse was observed after 49.4% of procedures; in 50% of the cases, recurrence occurred at 27 months (median follow-up) (Fig. 3). After the recurrence, it was necessary to perform BTUR in 13 patients (22.03%), of which only 3 (5.08% of the total of patients) presented progression (either of stage, grade, or both) although in no case was progression observed to a muscle-infiltrating bladder tumor. Two of these patients presented progression after a second fulguration. Of the 6 patients with a history of bladder neoplasm T1G1-2, only one patient had recurrence after fulguration, performing subsequent BTUR with CIS finding in the anatomopathological study. Significant differences in the time to recurrence were observed from the treatment of the first tumor (median 56 months) as opposed to time to recurrence from the treatment of a second tumor (median of 10 months) (LogRank test p < 0.0001) (Fig. 4). The median time to recurrence between the group of patients who were smokers was 25 months and 28 months for patients who were not. This difference was not statistically significant (LogRank test p = 0.389) (Fig. 5).
Age of the patients and elementary characteristics of the treated lesions.
Minimum Maximum Mean Standard deviation
Age (years)
Number of TUR
Number of lesions
Size of the lesion (mm)
45 86 66.29 10.631
1 6 1.59 .942
1 7 1.83 1.230
2 13 4.81 2.346
Outpatient Holmium laser fulguration
313 1,0
1,0
LogRank test p=0.389
LogRank test p<0.0001 Relapse after first tumor
0,8
Cumulative survival
Cumulative survival
0,8
0,6
0,4 Relapse after second tumor
0,6 Non-smoker
0,4 Smoker
0,2 0,2 0,0 ,00
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Follow-up
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Figure 4 Recurrence after fulguration of a first and a second tumor. Survival curve (months).
Discussion Although BTUR represents the standard treatment of NMIBT, during the last two decades, a search and implementation of alternatives in the management of recurrences of low-grade NMIBT has been carried out in order to reduce the number of surgical interventions that these patients undergo and, in this way, reduce the costs and morbidity derived from hospital admission and surgery. Among these alternatives to BTUR, we find laser fulguration, ‘en bloc’ ® laser resection, ‘en bloc’ resection with Hybrid Knife ,9 fulguration with electrical energy, and active surveillance. Fulguration under local anesthesia is an alternative to the BTUR recognized in the clinical practice guidelines of the European Association of Urology (EAU)10 and the American Association of Urology (AUA)11 in patients with a history of low-risk tumors and papillary recurrences of small size. In our experience, Holmium laser fulguration under local anesthesia and immediately subsequent instillation of MMC on an outpatient basis has proved to be a feasible alternative to BTUR in patients with selected tumors. As published in a pilot study12 and in line with other publications,13---15 in our center, the outpatient procedure and with the aforementioned local anesthesia protocol it was effective, well tolerated, and associated with a low risk of subsequent complications. Traditionally, the potential advantages of Holmiun laser fulguration versus BTUR in the most fragile patients (more advanced age, more comorbidities) from the point of view of diminishing the anesthetic, surgical risk, and complications associated with admission have been more relevant.13 However, in our study, we also decided to include young patients (mean age 66.2 years, range 45---86) and with fewer comorbidities since this group of patients will be subject, presumably, to a longer follow-up period and may benefit from the decrease in the number of conventional surgeries without increasing the risk of progression. From the oncological point of view, at 12 months, relapse was observed after 27.3% of the procedures, in contrast
Figure 5 Recurrence after fulguration in the group of smokers versus non-smokers. Survival curve (months).
to the results obtained by Wong, KA and collaborators,13 who present 65.1% and 46.9% in patients with conventional cystoscopy and with photodynamic diagnosis (PDD), respectively. This lower rate of recurrence in our study could be explained by the performance of a post-procedure MMC instillation and by the lower heterogeneity of our series in terms of previous histology, given that in the Wong series, KA includes patients with high-risk tumors. (T1G3, CIS) and muscle-invasive (T2G3) with small-sized recurrences in patients with a high surgical risk. Although in our series we did not use PDD since it is not available in our center, its use could possibly improve the detection of non-visible lesions with conventional cystoscopy and, therefore, decrease the risk of relapse after fulguration. This lower rate of recurrence in our study could be explained by the performance of a post-procedure MMC instillation and by the lower heterogeneity of our series in terms of previous histology, given that in the Wong series, KA includes patients with high-risk tumors (T1G3, CIS) and muscle-invasive (T2G3) with small-sized relapses in patients with a high surgical risk. Although in our series we did not use PDD since it is not available in our center, its use could possibly improve the detection of non-visible lesions with conventional cystoscopy and, therefore, decrease the risk of relapse after fulguration. The results of Hossain MZ and collaborators16 draw attention, who present a series of 30 cases of recurrent (n = 18) and primary (n = 12) tumors treated under spinal anesthesia by ablation (tumors <1 cm) and resection (tumors 1---4 cm) with Holmium laser, without the appearance of any recurrence in the first 6---12 months of follow-up. More similar to our results are those of de PlanellesGómez et al.17 in their series of 130 Holmium laser fulguration procedures under local anesthesia, in which patients with a history of low, intermediate, and high-risk tumors are included, with 20% of relapses in the first 6 months of follow-up. The decrease in the time free of recurrence in patients after the second fulguration compared to patients after the
314 first fulguration is remarkable (median: 10 vs. 56 months). Probably, it would be convenient to perform a BTUR in patients in whom relapse is observed after fulguration since this group of patients is the one with the highest risk of progression. Some authors18,19 have proposed active surveillance as an alternative to immediate BTUR after the diagnosis of relapse; that is, postpone the BTUR until the patient presents criteria to exit the protocol (increase in the number of lesions or growth of these, appearance of positive cytologies or symptoms). In the most extensive active surveillance study published so far, Hernández and colleagues present a series of 252 periods of active surveillance in 186 patients between 1999 and 2014, with a median follow-up of 6 years. Although the median time that the BTUR could be postponed was 13.4 months and 22 patients (8.7%) remained in active surveillance for more than 3 years, 4 patients had progression to T2G3 (2 of them with involvement of lymph nodes). Although laser fulguration prevents the collection of histological material and we cannot assure the absence of progression in the majority of our patients due to the absence of anatomopathological analysis in the vast majority of cases, the appearance of the lesion in cystoscopy can be informative enough to identify recurrent, non-invasive, and low-grade papillary tumors.20 From the economic point of view, Wong13 and collaborators present in their series a cost-effectiveness analysis with which they conclude that, for the £30,000/QALY threshold established by the National Institute for Health and Care Excellence (NICE), outpatient fulguration is a cost-effective procedure with a probability of 81.9%. Although a formal analysis of the procedure costs has not been carried out in the present study, we can estimate the number of operating room and hospital stay days avoided in our center. Given that the average postoperative stay after BTUR in our Department is 4 days and that usually 4 patients can be operated per day of the operating room, we can estimate that thanks to the treatment by outpatient fulguration, between 260 and 340 days of hospital stay and between 16 and 21 days of surgery were avoided, approximately. These data are illustrative and may vary in centers with different surgical activity and different postoperative average stay.
Conclusions Fulguration with Holmium laser under local anesthesia and subsequent instillation of MMC in outpatient regimen is a safe and feasible alternative to BTUR in patients with small papillary recurrences and a history of low risk NMIBT. It is probably advisable to perform a BTUR in patients with relapse after fulguration, since the risk of progression in this group of patients is possibly higher.
Conflict of interest The authors declare that they have no conflict of interest.
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