Neoadjuvant Gemcitabine-Cisplatin before Radical Cystectomy Versus Radical Cystectomy Monotherapy in Treatment of Muscle Invasive Bladder Cancer

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1 Med. J. Cairo Univ., VoL 81, No. 2, March: , Neoadjuvant Gemcitabine-Cisplatin before Radical Cystectomy Versus Radical Cystectomy Monotherapy in Treatment of Muscle Invasive Bladder Cancer MOHAMMED A. BADAWY, M.D.*; NASHWA NAWAR, M.D.*; MAHER EDAROS, M.D.*; AREF MAAROUF, M.D.; EHAB R. ELSAYED, M.D. and SALEM KHALIL, M.D.** The Departments of Clinical Oncology & Nuclear Medicine* and Urology**, Faculty of Medicine, Zagazig University, Egypt Abstract Objective: To evaluate the role of neoadjuvant gemcitabine and cisplatin before radical cystectomy compared to radical cystectomy monotherapy in patients with muscle invasive bladder carcinoma. Material and methods: This prospective study included 74 patients with muscle invasive transitional cell carcinoma (TCC) of the urinary bladder. Inclusion criteria were clinical stage (ct2-t4a, NO, MO), ECOG Performance score of 0-2, no previous radiotherapy or chemotherapy and no contraindication to radical surgery. Patients were randomized into two treatment groups: Group I (41 patients) received four cycles of gemcitabine-cisplatin (GC) before cystectomy and group II (33 patients) treated with radical cystectomy alone. Post cystectomy pathological stage was recorded. Patients were followed-up regularly for a minimum of three years. Cancer progression and cancer related mortality were recorded. Results: Out of 41 patients of group I, only 36 patients completed neoadjuvant GC. Pretreatment patient criteria were comparable among both groups. Mean patient age was 62 and 59.5 years for group I and II respectively. CT3 was the most prevalent pretreatment clinical stage. Neoadjuvant GC therapy was well tolerated in most of cases, with no severe acute toxicities. Stage PTO in post-cystectomy specimen was significantly higher in group I than group II (pto 33.3% Vs 9%). The median follow-up was 43.5 and 41.6 months in group I and II respectively. Tumor relapse was significantly lower in group I (16.7%) compared to group II (45.5%). Three year progression free survival rate in GC group was 91% compared to 71% in cystectomy group. Conclusion: Neoadjuvant chemotherapy with GC is effective in down-staging of the bladder tumors and improves progression-free survival after radical cystectomy. The combination of GC is well-tolerated with reduced toxicity profile. Key Words: Neoadjuvant Gemcitabine cisplatin Radical cystectomy Monotherapy Bladder cancer. Correspondence to: Dr. Mohammed A. Badawy, The Departments of Clinical Oncology & Nuclear Medicine, Faculty of Medicine, Zagazig University, Egypt Introduction MUSCLE invasive bladder cancer is still challenging to urologists, medical oncologists and patients facing this upsetting disease [11. Radical cystectomy with pelvic lymphadenectomy nowadays is considered the most effective treatment option [2]. Despite advances in surgical and peri-operative care, up to 50% of patients still develop tumor recurrence, suggesting that a considerable percentage have micrometastases at the time of surgery [31. The rationale for chemotherapy before cystectomy is to treat micrometastases away from the margins of local therapy already present at the time of diagnosis. Theoretically, the administration of chemotherapy before and not after surgery has several advantages; it is better tolerated, and may downstage the tumor so makes surgery more feasible and effective [2]. Neoadjuvant MVAC (Methotrexate, Vinblastine, Doxorubicin, Cisplatin) before cystectomy has been compared with cystectomy alone in several randomized trials. Despite excellent oncologic outcome, toxicity had been a major concern for MVAC therapy, and limits its clinical use [7,8]. Recently, a less toxic regimen of gemcitabine and cisplatin (GC) substituted MVAC as neoadjuvant protocol before radical cystectomy [9]. When used in metastatic disease, GC achieved similar response rates and survival as MVAC but with a better toxicity profile [101. In this study, we reported our experience with neoadjuvant Gemcitabine Cisplatin (GC) before radical cystectomy compared with radical cystectomy alone in patients with locally advanced bladder carcinoma. 117

2 118 Neoadjuiant Gemcitabine-Cisplatin before Radical Patients and Methods This study was conducted in Urology and Clinical Oncology Departments Zagazig University Hospitals in the period from March 2007 to January Patient selection: Written consents were taken from all patients. Seventy four patients with muscleinvasive transitional cell carcinoma of the urinary bladder as proved by pathological examination after transurethral resection of a bladder tumor (TUR-BT) were enrolled in the study. Clinical tumor-node-metastases (TNM) stage ranged from (ct2-ct4a NO MO). All patients should have adequate renal (serum creatinine 2mg/d1), hepatic (total bilirubin level 1.2mg/d1 and aspartate aminotransferase and alanine aminotransferase levels time the upper limit of normal) and hematologic (WBCs >3000/ mm3, hemoglobin >10g/d1 and platelet count >15 x 104/mm3) assessment with absence of concurrent diseases precluding surgery. Performance status according to Eastern Cooperative Oncology Group (ECOG) was between 0-2. Patients with previous radio or chemotherapy were excluded. Contrast enhanced pelvi-abdominal computed tomography scans and chest X-ray were done for all patients. Patients were randomly allocated into two groups: Group I: Included 41 patients who received neoadjuvant chemotherapy in the form of gemcitabine-cisplatin (GC) before radical cystectomy. Group II: Included 33 patients who underwent radical cystectomy only without neoadjuvant chemotherapy. Chemotherapy regimen for group I: Gemcitabine-Cisplatin (GC) chemotherapy was given in the form of 4 cycles. Each cycle is of 21 days. Gemcitabine was given in a dose of 1000mg/m2 diluted in 250m1 normal saline with IV infusion over 30 minutes on days 1 and 8. Cisplatin was given in a dose of 75mg/m2 in 500m1 normal saline over 60 minutes on day 1. Adequate intravenous hydration was adopted with every cisplatin infusion. Laboratory tests were done to assess for any hematological, hepatic or renal toxicity during chemotherapy and accordingly the doses were adjusted. Cisplatin dose was adjusted based on creatinine clearance. If WBCs were less than 2000/mm3 or platelet count was below 7 x 104/mm3 or grade 3 or 4 adverse effects, gemcitabine administration on day 8 was either delayed or was completely omitted. Radical cystectomy: Radical cystectomy with bilateral standard pelvic lymphadenectomy was performed in all patients. Urinary diversions were either orthotopic neobladder or ileal conduits. Cystectomy specimens were examined. The rate and degree of tumor downstaging was determined for patients of both groups. The study end point was to: - Determine tumor down-staging effect of neoadjuvant GC. - Compare progression-free survival among both groups. - Assess the toxicity profile of GC. Disease-free survival was defined as the time from first chemotherapy to the appearance of local or regional disease, metastases, or death. Kaplan Meier curves for both survival and disease progression were done using NetCalc software version p-value <0.05 was considered significant. Results Preoperative patient criteria, were comparable among both groups (Table 1). The mean age at surgery was 62 and 58 years for group I and group II respectively. The most prevalent clinical stage in the study patients was ct3 (39% in group I and 54.5% in group II). Table (1): Preoperative patient criteria. Group I Group II p Age: Range Mean (sd) (6.2) (7.1) 0.1 Sex: Male (%) 35 (85.4%) 28 (84.8%) 1.0 Female (%) 6 (14.6%) 5 (15.2%) Clinical T stage at presentation: ct2 (%) 10 (24.4%) 6 (18.2%) 0.51 ct3 (%) 16 (39%) 18 (54.5%) 0.18 ct4a (%) 15 (36.6%) 9 (27.3%) 0.39 Interval from diagnosis to radical cystectomy (days) Five patients from group I discontinued neoadjuvant chemotherapy schedule and were excluded from the study. Two of them asked for cystectomy after the first chemotherapy cycle and the other three patients were excluded for worsening of renal function. So the total numbers of group I patients completed chemotherapy course was 36 patients.

3 Mohammed A. Badawy, et al 119 Tumor down staging in the post-cystectomy specimen is shown in (Table 2). The incidence of pto was significantly high (33.3%) in group I compared to 9% in group II patients (p=0.01). The incidence of positive surgical margins was 5% and 14% in group I and group II respectively. The median dissected lymph node count was 16 nodes. Despite clinical NO stage at initial diagnosis, positive lymph nodes were detected in cystectomy specimens as shown in (Table 3) the proportion of pathologically positive nodes was lower in GC group compared to cystectomy group and stage dependent. Adverse effects of GC were generally mild. Grade 3-4 toxicities were encountered in few patients as shown in (Table 4). The median follow-up was 43.5 and 41.6 months for groups I and II respectively. During follow-up, seven (19.4%) patients died in group I (3 due to disease progression, one due to compli- cated diversion, 2 secondary to AMI and one secondary to CVS). In group II twelve patients (33.3%) died (9 due to disease progression, one due to complicated diversion and 2 secondary to AMI). Concerning disease progression, (Table 5) showed relapse rate in each group. Kaplan Meier progression curves differ significantly in favor of GC group compared to RC group. Where 3 years progression free survival were 85% & 55% in group I & II respectively p=0.02 (Fig. 2). Overall median progression-free survival was 31 months and 25 months in group I and II respectively. For pto cases progression free survival was 42.6 and 37.1 months in group I and II respectively. While in cases with <pt2 it was 33.6 and 29.4 months. Three year disease specific survival rate in patients who completed GC course was 91% compared to 71% in cystectomy only group. Kaplan Meier survival curves differ significantly in favor of GC group p=0.002 (Fig. 1). Table (2): Tumor down staging. Clinical stage at diagnosis Pathological stage at cystectomy Group 1 Group II pto ptis pti pt2 pt3 pt4 Total pto ptis pti pt2 pt3 pt4 Total p=0.01 ct ct ct4a Total Table (3): Positive LN in both groups. Table (4): Drug related toxicity. pt2 1 pt3 2 pt4 4 Group I Group II P Toxicity Grade 1 Grade 2 Grade 3 Grade Total Table (5): Relapse rate. Relapse Group I Group II P Systemic 3 (8.3%) 8 (24.2%) 0.07 Concomitant local and systemic 2 (6%) 0.60 Local 5 (15.1%) 0.24 Total 6 (16.7%) 15 (45.5) 0.009* p<0.01(hs) Hematologic: Neutropenia 9 (25%) Anemia 6 (16.6%) Thrombocytopenia 8 (22.2%) Nausea &vomiting: 12 (33.3%) Fever - Mucositis Fatigue 8 (22.2%) 7 (19.4%) 4 (11.1%) 11 (30.5%) 8 (22.2%) 3 (8.3%) - 4 (11.1%)

4 120 Neoadjuiant Gemcitabine-Cisplatin before Radical Survival probability (%) f fffilf Time Numbar at risk Group 1: Group 2: Survival probability (%) Death Group L LI II L LI Fig. (1) Proression Group i fitivt-tt1i Time Numbar at risk Group 1: Group 2: Fig. (2) Discussion The standard treatment for muscle-invasive bladder cancer is radical cystectomy, however, the risk of recurrence after surgery is high and stage dependent with an overall 5-year survival of only 50% [11-15]. In order to improve these inadequate results, the use of peri-operative chemotherapy has been studied since the 1980s. Several studies investigated the question of whether or not neoadjuvant chemotherapy improved survival, with conflicting results [4,16-18]. In this study we investigated the effect of neoadjuvant chemotherapy using GC on pathologic down-staging and progression-free survival of patients with muscle invasive bladder cancer as compared with radical cystectomy monotherapy. The rationale behind using GC was the proven long-term oncologic outcomes with lower 1 toxicity profile as compared to the standard MVAC in patients with metastatic bladder cancer therapy [19,20]. In our study we used a 21-day schedule for 4 cycles which was tolerated by 88% of cases. This is not far from that reported by Dash et al. [21]. where (93%) of patients tolerated 4 cycles. Our findings suggests that this chemotherapy regimen is capable of down-staging the tumors inside the bladder and improves the postcystectomy survival rates. Stage pto was achieved in 33.3% of patients receiving neoadjuvant GC compared with 9.1% of patients in the cystectomyonly group. No residual muscle-invasive disease (<pt2, ie, pto, ptis, pt1) was reported in 47.2% in GC group compared to 24.2% in cystectomy only group. This is somewhat higher than the proportions reported in the study done by Scosyrev et al. [221. Where pto at cystectomy was documented in 20% of patients in GC group and in 5% of patients in the radical cystectomy group. Bertram et al. [23] in their Pooled Analysis of seven studies with a total of 164 patients about Clinical Outcomes with Neoadjuvant Cisplatin and Gemcitabine Chemotherapy for muscle-invasive bladder cancer between 2007 and 2012 reported a pathologic down-staging to pto and <pt2 occurred in 42 (25.6%) and 67 (46.5%) patients, respectively. In a study Dash et al. [21] the proportion of patients with complete eradication of the tumor (pt0) was 26% and those with (<T2) was 36% in CG group compared to 33.3% and 47.2% in our study respectively. They also compared their results with local MVAC records and found a comparable oncologic efficacy (T0=28% and <T2=35%). Fairey et al. [24] retrospectively compared neoadjuvant CG versus MVAC and concluded that Pathologic and survival outcomes did not differ in patients who received neoadjuvant GC and M- VAC and support the use of the GC regimen in the neoadjuvant setting. In the present study the incidence of positive surgical margins was 5% in CG group and 14% in cystectomy group. This was not matching reports of Scosyrev et al. [22] who reported 12% positive margins in CG group versus 11% in cystectomy only group. In our study, the median dissected lymph node count was 16 nodes. Despite clinical NO stage at initial diagnosis, N1 stage was lower in CG group (7 pts) compared to cystectomy group (9 pts). Similarily to our results Scosyrev et al.

5 Mohammed A. Badawy, et al 121 [22] reported no beneficial effect of neoadjuvant CG where N+ stage was reported in 44% of CG compared to 43% in cyetectomy only group. The cause of these high figures of N+ cases could be attributed to the inclusion of any N stage in their patients selection compared to clinical NO in our study. Scosyrev et al. [22] concluded that despite being capable of down-staging tumors in the bladder, neoadjuvant GC; however, had no effect on disease in nodes. In the pooled analysis made by Bertram et al. [23] 29.7% of patients were found to have pn1 disease after CG neoadjuvant therapy, a result which is higher than reported in our study. This high pn1 could be related the lack of definition of Pretreatment N stage in this study. When toxicity profile is considered, the present study reported grade 3-4 neutropenia, anemia and thrombocytopenia in 5.5%, 2.7% and 8.2% of patients respectively. This was lower than the figures reported by Kaneko et al. Who reported grade 3-4 neutropenia, anemia and thrombocytopenia in 14.3%, 2.4% and 21.4% of patients respectively [25]. Herchenhorn et al. [26] reported a 38% incidence of grade 3-4 hematologic toxicity a figure which is higher than 16.2% reported in our study. In the current study, the incidence of tumor relapse was 16.6% in patients receiving GC compared with 45.4% in the cystectomy only. A figure which is much lower than 42.5% reported with GC in the study done by Herchenhorn et al. [26]. In our study median progression-free survival was 31 months and 25 months in GC group and cystectomy group respectively. For pto cases progression free survival was 42.6 and 37.1 months in CG and RC group respectively. While in cases with < pt2 Progression free survival was 33.6 and 29.4 months in CG and RC group respectively. This is nearly similar to that reported with Dash et al. [21] where all their 15 GC patients achieving <pt2 pathologic stage remained disease-free at a median follow-up of 30 months. In the study of Herchenhorn et al. [26] Median progression-free survival was 27 months with neoadjuvant CG. In the present study, three year progression free survival rate in patients who completed GC course was 91% compared to 71% in cystectomy only group. Kaplan Meier survival curves differ significantly in favor of GC. This favorable results with neoadjuvant GC were in accordance to what reported with Wosnitzer et al. [27]. Who demonstrated a statistically significant improvement with disease specific survival in patients receiving neoadjuvant CG compared to adjuvant CG. Finally, this study is an addition to the published literature in the field of neoadjuvant GC in muscle invasive bladder carcinoma. 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