UROLOGICAL ONCOLOGY The Rate of Neoadjuvant Chemotherapy Use in Muscle Invasive Bladder Cancer and The Approach of Urologists in Turkey Oktay Ucer1*, Ali Can Albaz1, Elif Atağ2, Aziz Karaoğlu2, Talha Muezzinoglu1 Purpose: To investigate the proportion of neoadjuvant chemotherapy (NAC) use in patients with muscle invasive bladder cancer before radical cystectomy and the approach of urologists to this subject. Materials and Methods: We invited 242 urologists during the 12th International Urooncology Congress in Turkey to answer a self-administered questionnaire. The questionnaire included questions related to radical cystectomy, lymph node dissection and neoadjuvant chemotherapy that had been performed in patients with muscle invasive bladder cancer by the urologist. Results: The median number of radical cystectomy operations was 20 per year. 122 (50.5 %) of 242 urologists had used neoadjuvant chemotherapy for the treatment of muscle invasive bladder cancer before radical cystecto- my. The mean rate of neoadjuvant chemotherapy use by these urologists (n=122) was 28.46 %. The most common reasons for not using neoadjuvant chemotherapy by urologists in Turkey were as follows: (i) neoadjuvant chemo- therapy might lead to a decrease in the cure rate of radical cystectomy due to delayed surgery (ii) complication rate of radical cystectomy might be elevated and the surgery might be complicated by NAC use. Conclusion: Although the European Association of Urology (EAU) guidelines panel on muscle invasive bladder cancer recommends using NAC in T2-T4a bladder, the rate of neoadjuvant chemotherapy use was still found to be low in our country because urologists have concerns about adverse effects NAC on radical cystectomy. Keywords: bladder cancer; chemotherapy; neoadjuvant treatment INTRODUCTION Bladder cancer (BC) is a worldwide problem, as being the fourth most common cancer in men and the eighth one in women and 80% of all BC patients are males (1). Worldwide estimates suggest that approxi- mately 330,000 cases are diagnosed with BC each year, and 123,000 patients will die due to this cancer(2). The most common histological types of BCs are transition- al cell or urothelial carcinoma, constituting 90% of all BCs and 30% of these casesmare muscle invasive bladder cancer (MIBC) at the time of initial diagnosis. Radical cystectomy (RC) and pelvic lymph node dis- section are considered to be the gold standard treatment for MIBC (3). Although this treatment may be curative, a large proportion of the patients will harbor micromet- astatic disease, contributing to recurrence rates of up to 40% at 5 years(4). An early study of Southwest Oncol- ogy Group demonstrated that radiotherapy before RC did not change the results(5). Therefore systemic chemo- therapy has been investigated as a treatment option in both neoadjuvant and adjuvant settings since the 1980s. Although the data supporting adjuvant chemotherapy are insufficient, neoadjuvant chemotherapy (NAC) that includes cisplatin-based combination therapy is recommended for MIBC by the guidelines for mus- cle invasive and metastatic bladder cancer of the Eu- ropean Association of Urology(6). Although according to the American National Cancer Database records, only 1.2 % of patients with MIBC received neoadju- vant chemotherapy between 1998 and 2003(7), this rate was reported as 12 % by Feifer et al. in 2011(8). Despite the recommendation of NAC use in MIBC and the outcomes of randomized trials, the rate of pa- tients receiving NAC has increased only quite a little(6). The aim of the present study was to investigate the rate of NAC use in patients with MIBC before radical cystectomy and the approach of urologists to this subject in Turkey. MATERIALS AND METHODS Three hundred and ten urologists, who participated in 12th International Urooncology Congress (total num- ber of participants was about 750) between 18th and 22nd of November 2015 in Antalya-Turkey, filled out a self-administered questionnaire. Two hundred and forty two of the 310 participants who were working in Turkey were enrolled in the study. 68 urologists were excluded from the study either because they did not perform radical cystectomy in their clinics or did not completely fill in the questionnaire form. The study questionnaire was developed by the study team and consisted of three parts as follows:(1) so- cio-demographic data;(2) five questions about how the urologists performed radical cystectomy procedure in their clinics;(3) four questions about their prefer- ence for NAC use for the treatment of MIBC. If they 1Celal Bayar University, Faculty of Medicine, Department of Urology, Manisa, Turkey. 2Dokuz Eylül University, Faculty of Medicine, Department of Medical Oncology, Izmir,Turkey. *Correspondence: Celal Bayar University, Faculty of Medicine, Department of Urology, Manisa - TURKEY. Tel: +905052114618. E-mail: uceroktay@yahoo.com. Receiveed February 2016 & Accepted August 2016 Urological Oncology 2841 answered that they did not choose to give NAC then they were asked why they did not prefer to use it. Statistical analysis was performed using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). The demographic data and responses to the questions were statistically eval- uated. The participants were divided into two groups according to whether they used NAC or not and into three groups according to their responses (yes, no or I do not know) to the question "Do medical oncolo- gists recommend NAC in your hospital?" The groups were statistically compared by using the Chi-square test. Statistical significance was considered at P < .05. RESULTS Two hundred and forty two of the 310 participants were enrolled in the study. 68 urologists (21.9%) were ex- cluded from the study either because they did not per- form radical cystectomy in their clinics or did not com- pletely fill in the questionnaire form. The demographic data of urologists in this study is presented in Table 1. The median number of radical cystectomy operations was 20 (2-200) per year. All the participants performed lymph node dissection during radical cystoprostatec- tomy. The rate of lymph node dissection during radi- cal cystectomy was 100 %. The mean rate of extended lymph node dissection was 65.05 ± 3.64 (0-100). 122 of 242 urologists performed NAC before radical cystecto- my for the treatment of MIBC. The mean rate of NAC use was 28.46 % ± 24.39 % (5-100%). 120 urologists, who did not use NAC were asked, why they did not use NAC. The distribution of responses to this ques- tion is summarized in Table 2. The responses to two questions about their urooncologic council and medical oncologists’ approach in their hospital are summarized in Table 3. Logistic regression was used to assess the effect of potentially relevant factors on the NAC use. We found that the participants who worked with med- ical oncologist that recommended NAC used NAC 3.24 (2.19 - 4.79) times more than other participants. DISCUSSION The risk of recurrence following RC for the treatment of MIBC is high and correlates with pathologic stag- ing(9). Although RC is gold standard, it provides 5-year survival only in approximately 50 % of patients(6). Despite this gold standard treatment, patients with MIBC face a 50% chance of recurrence(10). Some au- thors suggested that the predominant cause of this high recurrence rate was occult micro-metastases present at the time of RC(1). NAC has been investigated for last three decades for their effect in MIBC. There are many advantages of NAC for the patients with MIBC, including: (1) chemotherapy is delivered at the earli- est time-point and allows for earlier exposure of mi- cro-metastatic cells to chemotherapeutic agents;(2) we can determine the chemosensitivity of tumor cells in vivo; and(3) patient compliance and tolerability are better before RC than after it(6). The most recent me- ta-analysis with updated results from 11 randomized trials (n = 3005) detected a significant survival benefit associated with platinum based combination chemo- therapy for the treatment of MIBC before RC(11). The results of this meta-analysis showed a 5 % absolute im- provement in survival at 5 years. Similarly, the Nordic combined trial showed an 8 % absolute improvement Chemotherapy in bladder cancer in Turkey-Ucer et al. Table 1. Demographic data of urologists in the study Age (years) N % 20-30 38 15.7 31-40 66 27.2 41-50 76 31.5 51-60 45 18.6 > 60 17 7.0 Degree Urology specialists 55 22.7 Assistant Professor 32 13.2 Associated Professor 68 28.1 Professor 87 36.0 Institution University 153 63.2 Training and research hospital 68 28.1 Private hospital 21 8.7 No Responses to the question N % 1 It may decrease the chance of cure because of delayed RC 21 17.5 2 It may complicate RC and increase the complications of surgery 21 17.5 3 Adjuvant chemotherapy is more effective than neoadjuvant 12 10 4 I do not believe in the effectiveness of neoadjuvant chemotherapy 7 5.8 5 1+2 35 29.2 6 1+3 5 4.1 7 1+4 5 4.1 8 Others 14 11.8 Total 120 100 Abbreviation: RC, Radical cystectomy Table 2. Responses to the question “why not do you use neoadjuvant chemotherapy before radical cystectomy for the treatment of muscle invasive bladder cancer”. Vol 13 No 05 September-October 2016 2842 in survival at 5 years and 11 % in the cT3 disease(3). The largest randomized trial with a median follow–up of 8 years confirmed these results. This trial showed that NAC (cisplatinum, metotrexate and vinblastine) in- creased the 10 years survival rate from 30% to 36%(12). Despite these benefits of platinum based NAC, most urologists still do not use it before surgery(8). Actually use of NAC has been rising in the last decades global- ly, but it still remains underutilized. In a retrospective study, Krabbe LA et al. reported that the usage of cis- platin-based NAC increased from 17% to 35% between 2008 and 2012(13). In a larger data set from National Cancer Database in USA, it was reported that use of NAC in MIBC increased from 13% in 2007 to 21% in 2010(14). In our study, the mean rate of NAC adminis- tration by urologists was found to be 28.4%. This result is higher than the rates reported in the older studies(7,8), but it is similar to some contemporary series(13,14). We do not have any historical data for use of NAC in our county. Therefore we could not compare our result with any historical Turkish series. In this study we found a good rate for NAC in MIBC but this rate is still low. The two most common reasons that urologists claim for not using NAC are as follows: (i) it may decrease the chance of cure because of delayed RC and (ii) it may complicate RC and increase the complications of surgery. 72.4% of the urologists participating in this study chose one of these two responses to the question “Why don’t you use NAC ? ”. In fact, the results of the combined Nordic trial responded to the concern of urologists regarding the adverse effect of NAC on RC(3). The results showed that NAC did not have any major influence on the percentage of performa- ble RC. The cystectomy frequency in all patients al- located to the NAC arm was 86% and in the control arm was 87%. Three studies that investigated the ef- fect of NAC on perioperative mortality and morbidi- ty were published in 2014(15-17). The findings of these studies showed that NAC was not associated with an increase in perioperative complications or death. The other most common concern of urologists in our study was that it might decrease the chance of cure be- cause of delayed RC. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer reported a significant survival benefit of NAC for the treatment of MIBC and recommend it for T2- 4a, N0M0 bladder cancer. Delayed RC may influence only patients, who are not sensitive to chemotherapy. However, there are no studies, which show that delayed RC due to NAC, can have a negative impact on sur- vival(6). Therefore, the fears of urologists, who did not use NAC before RC are unwarranted in fact. The main problem regarding the use of NAC is actually risk of overtreatment. However, none of the urologists in our study mentioned this as a concern for not using NAC. Bimanual palpation, computerized tomography and magnetic resonance imaging are often used for diagno- sis of bladder cancer. Clinical staging using these mo- dalities may result in both over and under-staging and lead to a staging accuracy of only 70%(18,19). Thus, over- treatment or undertreatment is possible for some cases. In the present study, we also assessed the effects of medical oncologists and regular meetings of multidisci- plinary urooncologic council on the preference of urol- ogists with regard to NAC use. There was no signifi- cant relationship between the preferences of urologists and regular meetings of multidisciplinary urooncologic council, on the other hand there was a significant rela- tionship between the preference of urologists and the recommendation of medical oncologists (Table 3). The recommendations of medical oncologists that worked in the same hospital with urologists who preferred to use NAC and who did not, were 85.2% and 34.4%, respectively (P < .001). Also the results of logistic re- gression indicated that the NAC use frequency of par- ticipants who worked with medical oncologist who recommended NAC was 3.24 (2.19 - 4.79) fold higher than those who did not. This result shows that recom- mendation of medical oncologists plays an important role in the preference of urologists regarding NAC. A limitation of our study was that the rate of NAC use was only determined according to the written statement of urologists. If this rate was calculated with data obtained from hospital archives, the results could be more reliable. CONCLUSIONS The findings of our study shows that the rate of NAC use before RC in our country was low despite the strong recommendations of urology guidelines. The reasons for the reluctance to use NAC are found to be con- cerns about: A) the fear that NAC may decrease the chance of cure due to delayed RC and B) increase in surgical mortality and morbidity. There are many ev- idences showing that NAC does not lead to these sit- uations in the literature. We suggest that it should be emphasized that these concerns about NAC are un- Urological Oncology 2843 Table 3. The comparison of the responses to the two questions about their urooncologic council and aspect of medical oncologists in their hospital. Do you use neoadjuvant chemotherapy? N (%) P value Yes No Total Does an urooncology council regularly meet in your hospital? N (%) Yes 91 (74.5) 79 (64.7) 170 (70.2) 0.51 No 31 (25.5) 41 (35.3) 72 (29.8) Total 122 (100) 120 (100) 242 (100) Do medical oncologists recommend neoadjuvant Yes 104 (85.2) 42 (34.4) 146 (60.4) < 0.001 chemotherapy before radical cystectomy in your hospital? N (%) No 3 (2.4) 45 (36.8) 48 (19.8) I do not know1 5 (12.4) 33 (28.8) 48 (19,8) Total 122 (100) 120 (100) 242 (100) Chemotherapy in bladder cancer in Turkey-Ucer et al. warranted and the recommendations of the current guidelines by urology associations should be reminded in congresses or via internet. In addition, we recom- mend that urologists and medical oncologists should be working in collaboration for the treatment of MIBC. REFERENCES 1. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349: 859-66. 2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90. 3. Sherif A, Holmberg L, Rintala E, et al. Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 2004; 45: 297-303. 4. Hautmann RE, de Petriconi RC, Pfeiffer C, et al. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol 2012; 61: 1039-47. 5. Smith JA Jr, Crawford ED, Paradelo JC, et al. Treatment of advanced bladder cancer with combined preoperative irradiation and radical cystectomy versus radical cystectomy alone: a phase III intergroup study. J Urol 1997; 157: 805-7. 6. Witjes JA, Compérat E, Cowan NC, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 2014; 65: 778-92. 7. David KA, Milowsky MI, Ritchey J, et al. Low incidence of perioperative chemotherapy for stage III bladder cancer 1998 to 2003: a report from the National Cancer Data Base. J Urol 2007; 178: 451–4. 8. Feifer A, Taylor J, Shouery M, et al. Multi- institutional quality-of-care initiative for nonmetastatic, muscle-invasive, transitional cell carcinoma of the bladder. J Clin Oncol 2011;29 (suppl 7; abstr 240). 9. Stein JP, Skinner DG. Radical cystectomy for invasive bladder cancer: long-term results of a standard procedure. World J Urol 2006; 24: 296-304. 10. Porter MP, Kerrigan MC, Donato BM, et al. Patterns of use of systemic chemotherapy for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol 2011; 29: 252-8 11. Advanced Bladder Cancer (ABC) Meta- analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta- analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol 2005; 48: 202-205 12. International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011; 29: 2171-7. 13. Krabbe LM, Westerman ME, Margulis V et al. Changing trends in utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer. Can J Urol. 2015; 22: 7865-75. 14. Zaid HB, Patel SG, Stimson CJ et al. Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database.Urology. 2014; 83: 75-80. 15. Johnson DC, Nielsen ME, Matthews J, et al. Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. BJU Int 2014; 114: 221-8. 16. Gandaglia G, Popa I, Abdollah F, et al. The effect of neoadjuvant chemotherapy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population-based study. Eur Urol 2014; 66: 561-8. 17. Tyson MD, Bryce AH, Ho TH, et al. Perioperative complications after neoadjuvant chemotherapy and radical cystectomy for bladder cancer. Can J Urol 2014; 21: 7259-65. 18. Sternberg CN, Pansadoro V, Calabrò F, et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer 2003; 97: 1644-52. 19. Herr HW, Scher HI. Surgery of invasive bladder cancer: is pathologic staging necessary? Semin Oncol 1990; 17: 590-7. Chemotherapy in bladder cancer in Turkey-Ucer et al. Vol 13 No 05 September-October 2016 2844