Is TURBT able to cure high risk recurrent superficial or muscle invasive bladder cancer : Factors resulting in pT 0 radical cystectomy specimens

ARtIclE INFO _________________________________________________________ ___________________ Vol. 39 (3): 364-370, May June, 2013 doi: 10.1590/S1677-5538.IBJU.2013.03.09 IBJU | factorS for pt0 radical cyStectomy 365 reported no survival advantage (6) most of them reported excellent long-term survival rates for patients with tumor downstaging (1,5,7-11). The inclusion of patients who have been treated with neoadjuvant chemotherapy (NAC) and/or radiotherapy (5,6,8,10) complicates the interpretation of the results of these studies. Our aim was to perform an analysis in our series (our center is a regional cancer center covering a population over 2 million) of radical cystectomies in order to determine which factors caused downstaging and particularly the absence of tumor at radical cystectomy. That obviously means that such tumors were in fact cured by just a TURBT from a surgical perspective. MAtERIAlS AND MEtHODS We retrospectively reviewed the final pathological result of all 51 radical cystectomies performed in our institution over the last 10 years (January 2002 until January 2012). Five pT0 radical cystectomies were discovered while patient and operative notes were thoroughly reviewed by two reviewers. Emphasis was placed when reviewing the notes on the initial TURBT pathology specimen, the surgeon who performed the TURBT and the details of the operation, whether any neo-adjuvant treatment (e.g. chemotherapy) was administered etc. Special attention was placed on the TURBT pathology specimen and thorough re-discussion with an uro-pathologist about all specimens was done. Factors that might have contributed to a pT0 cystectomy specimen were disclosed and a systematic review of the available literature (all articles in PubMed were searched including non-English publications using the keyword ‘pT0 radical cystectomy’) was performed in order to present possible factors leading to such favorable cystectomy specimens.


INTRODUCTION
Radical cystectomy (RC) with pelvic lymph node dissection is the gold standard for treatment of muscle invasive bladder cancer (MIBC) as well as high risk superficial bladder cancer.In about 76% of patients there is discrepancy between the initial clinical T-stage (cT-stage) at transurethral resection of the bladder tumur (TURBT) and the final pathology (pT-stage) after RC (1).Factors that may be responsible for such discrepancy may be poor sensitivity of current image exams, incomplete TURBT with undersampling of muscle tissue or a long interval between TURBT and RC (2,3).Clinical understaging of the tumor is reported in 40-49% of RC (1,4) while clinical overstaging occurs in 20-27% of RC (1,5).Up to 30% of patients with MIBC at the time of TURBT have non-MIBC at RC specimen (5).
There are several reports on the effect on prognosis of tumor downstaging from MIBC at TURBT to non-MIBC at RC.Although one study reported no survival advantage (6) most of them reported excellent long-term survival rates for patients with tumor downstaging (1,5,(7)(8)(9)(10)(11).The inclusion of patients who have been treated with neoadjuvant chemotherapy (NAC) and/or radiotherapy (5,6,8,10) complicates the interpretation of the results of these studies.
Our aim was to perform an analysis in our series (our center is a regional cancer center covering a population over 2 million) of radical cystectomies in order to determine which factors caused downstaging and particularly the absence of tumor at radical cystectomy.That obviously means that such tumors were in fact cured by just a TURBT from a surgical perspective.

MATERIALS AND METHODS
We retrospectively reviewed the final pathological result of all 51 radical cystectomies performed in our institution over the last 10 years (January 2002 until January 2012).Five pT0 radical cystectomies were discovered while patient and operative notes were thoroughly reviewed by two reviewers.Emphasis was placed when reviewing the notes on the initial TURBT pathology specimen, the surgeon who performed the TURBT and the details of the operation, whether any neo-adjuvant treatment (e.g.chemotherapy) was administered etc. Special attention was placed on the TURBT pathology specimen and thorough re-discussion with an uro-pathologist about all specimens was done.Factors that might have contributed to a pT0 cystectomy specimen were disclosed and a systematic review of the available literature (all articles in Pub-Med were searched including non-English publications using the keyword 'pT0 radical cystectomy') was performed in order to present possible factors leading to such favorable cystectomy specimens.

RESULTS
Five patients in our series (Table-1) submitted to radical cystectomy for bladder cancer had a final pathological stage of pT0 (no residual tumor).In all patients neither preoperative work-up (chest and computed tomography urogram) nor post--operative full lymph node dissection revealed any lymph node or metastatic spread.Four TURBT specimens were transitional cell carcinomas (TCC) and one was squamous cell carcinoma (SCC).The estimated macroscopic size of the TURBT tumor ranged from 5 mm to 4 cm.All operative notes from the TURBT reported a complete macroscopic clearance of the tumor with deep resection and additional biopsies from the tumor bed.No lymphovascular invasion was noted in none of the TURBT specimens.All the TURBTs were performed by two experienced senior urologists and the radical cystectomies were performed by 2 urological surgeons.The time from TURBT to radical cystectomy ranged from 120-210 days.Neo-adjuvant chemotherapy was administered to two patients.Follow-up after cystectomy ranged from 6 months to 69 months.Four patients are doing very well on follow-up.One died 45 months after the operation from other cause (cardiac event) and had no cancer recurrence.
The literature review resulted in 11 articles (Table -2) after excluding case reports and small series as well as irrelevant publications and duplicates.

DISCUSSION
Our series of pT0 radical cystectomies indicated a few factors that may be contributing to such a result (no tumor found on final cystectomy specimen).Obviously it would be very important to know if there are factors after a TURBT that should prompt treatment with bladder preservation strategies for muscle invasive or recurrent high risk superficial bladder cancer.This would obviously prevent patients from having a major operation like a radical cystectomy with urinary diversion, which have high morbidity and a deterioration in the quality of life.Herr (12) found a 10-year disease-specific survival of cT2 patients who were treated with re-TURBT of 76% (57% had eventually their bladder preserved) compared with 71% for those who had immediate radical cystectomy.Although initially an older study (6) found no advantage in cancer-specific survival for pT0 cystectomy patients (the study had low number of patients to draw statistically valid results) all subsequent studies (Table - It seems that a macroscopic complete resection as reported by the surgeon in the operative notes was a factor contributing to a pT0 specimen.It has been suggested in other studies (11,13) that a thorough and complete TURBT may be warranted in most patients who have even got an appearance of invasive tumor as when re-evaluating with a re-TURBT they may be candidates for bladder preservation especially if no residual tumor is present.Furthermore, a study (9) confirmed that patients with a cT2a tumor stage on TURBT had significantly better cancer-specific survival when a pT0 stage was achieved at RC (with the use of neo-adjuvant chemotherapy) compared with those who had residual cancer on RC.As others (14) have suggested a radical TURBT is probably not causative of the improved cancer-specific survival in pT0 cystectomy patients but rather individual tumor characteristics allow for complete tumor eradication, including small tumor size, unifocality and stage T2a.
Another factor that was evident, even in large tumors measuring 3-4 cm, was the absence of lymphovascular invasion which seemed to consistently produce final pT0 radical cystectomy specimens in our series.Another study (15) has  Yes ( 2) cTis (9%), cTa (4%), cT1 also underlined the role of lymphovascular invasion as an independent factor of advanced tumor stage, grade and shorter overall and recurrence--free survival.
There was a source of bias for two of our patients who received neo-adjuvant chemotherapy and that might have contributed to a favorable result, however, we have to take into account that chemotherapy is a non-invasive treatment and may consist part of a multimodality approach for bladder-preserving techniques.It has been demonstrated in one study (16) that the prognostic significance of a pT0 stage is independent of whether this was achieved by means of TURBT or neo-adjuvant chemotherapy.In the same study TURBT achieved a 15% pT0 rate at radical cystectomy, while neoadjuvant chemotherapy and TURBT achieved a 38% pT0 rate respectively.Others (7) claimed that neoadjuvant chemotherapy is not necessary or beneficial for downstaged cT2 tumors to pT0 by TURBT.On the contrary, another study (17) supported that patients who are pT0 after neoadjuvant chemotherapy are at higher risk of disease recurrence compared with those who achieve pT0 with TURBT alone (the explanation was that an increased rate of non-organ confined clinical stage was selected for chemotherapy in the study).
Furthermore, it has been found from studies that delay > 90 days for cystectomy is unfavorable (18) regarding prognosis.That was not confirmed in our study since even extreme delay up to 210 days did not affect the outcome.It seems that in three of our patients the TURBT cleared the tumor and in two more the addition of neo-adjuvant chemotherapy either consolidated such a result or eradicated any residual tumor.Other factors that have been mentioned in a study (19) which are associated with a worse outcome for pT0 cystectomy patients were females and patients with nodal spread, however, these could not be assessed in our series.Also, the presence of concomitant carcinoma in situ is associated with disease progression but could be treated with intravesical BCG and closer follow-up (20).
Experience of the surgeon performing the TURBT might also play a role.All our patients were operated by experienced surgeons (> 50 procedures) and a standardized procedure was performed with the aim of completely removing the whole tumor including deep resection and also biopsy of its base.The base was then thoroughly diathermised with a rolleyball.It has been suggested that a 'radical' transurethral resection is justified when the tumor is clinically limited to the muscular layer and when all biopsies of the periphery and the base of the tumor are negative for further muscular invasion (20).This offered an 80.5% cancer-specific survival in 5 years with a bladder preservation rate of 82.7% (20).
Bladder sparing techniques have included re-TURBTs (12), the use of chemotherapy and/or radiotherapy and also the use of re-TUR-BT with adjuvant radiotherapy and laparoscopic lymphadenectomy for high risk tumors (Grade 2 or 3) (21).One very important multi-institutional trial (SPARE trial) comparing selective bladder preservation versus radical excision was abandoned in 2010 due to poor accrual (22).The urological community has to learn by these mistakes and conduct relevant trials that will answer the important issue of bladder preservation.
The limitations of the study are that the number of patients is obviously small to extract valid statistical results but our aim was to identify in our series factors that would be worth investigating in a multi-institutional setting in order to increase validity.More than one surgeon performed the procedures but a standard operative technique was used as described earlier.

CONCLUSIONS
Four factors were identified in our study and could be investigated further: the absence of lymphovascular invasion and a complete resection which do have a favorable role, surgical experience and adherence to standardized techniques according to guidelines also contribute to such results.On the contrary, the time to cystectomy did not seem to have affected outcomes in our case series and that also remains to be confirmed.All these issues need to be clarified by the urologic community by designing and conducting multi--institutional randomized studies.
2) have shown an advantage in recurrence-free survival or cancer-specific survival.