Outcome in patients with exclusive carcinoma in situ (CIS) after radical cystectomy Pascal Zehnder*†, Felix Moltzahn†, Siamak Daneshmand*, Marya Leahy*, Jie Cai*, Gus Miranda*, Georg Bartsch Jr*, Anirban P. Mitra‡, Donald G. Skinner*, Eila C. Skinner* and Inderbir S. Gill* *Catherine & Joseph Aresty Department of Urology, USC Institute of Urology, and ‡Department of Pathology and Center for Personalized Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA, and †Department of Urology, University of Bern, Bern, Switzerland P.Z. and F.M. contributed equally
Objective • To evaluate oncological outcomes of patients with carcinoma in situ (CIS) exclusively at radical cystectomy (RC) and no previous history of ≥T1 disease.
Patients and Methods • Patients undergoing RC with curative intent for CIS between 1971 and 2008 at the University of Southern California were included if they met all the following criteria: (i) pathological CIS-only disease at RC, (ii) preoperative clinical stage cCIS and/or cCIS + cTa, and (iii) no previous history of lamina propria invasion (≥pT1). • Kaplan–Meier plots were used to estimate the probabilities of recurrence-free survival (RFS) and overall survival (OS).
Results • Of the 1964 consented patients 52 met the inclusion criteria with a median (range) follow-up of 8.5 (0.008–34) years. • A median (range) of 36 (10–95) lymph nodes were identified per patient but no metastases found.
Introduction Patients with carcinoma in situ (CIS) of the urinary bladder are at risk of progression to invasive disease and death if left untreated [1,2]. Attempts to control CIS with transurethral bladder resection (TURB) alone are unsuccessful in most cases, and therefore not considered an ideal therapeutic option. In contrast, intravesical instillation of the immunostimulant BCG has become the treatment of choice, as induction and maintenance therapy are associated with reduced recurrence and risk of progression [3]. Despite this, a considerable proportion of patients may primarily fail to respond while others recur during the course of conservative treatment. There is no clear consensus for further therapeutic management of patients with recurrent CIS of © 2013 The Authors BJU International © 2013 BJU International | doi:10.1111/bju.12250 Published by John Wiley & Sons Ltd. www.bjui.org
• Estimated 5- and 10-year RFS rates were 94% and 90%, respectively and estimated 5- and 10-year OS rates were 85% and 66%, respectively. • Different mechanisms of recurrence were found in four (8%) patients after a median (range) interval of 2.4 (0.6–7.1) years. While two patients had metachronous recurrence within the urinary tract, the first of the other two had early systemic recurrence and the second late local recurrence.
Conclusions • We noticed excellent outcomes after RC for CIS-only disease. • However, patients may have synchronous and/or develop metachronous tumours, as well as local and/or distant/systemic recurrence that can be cured but may also lead to fatal outcomes.
Keywords bladder cancer, carcinoma in situ, radical cystectomy, carcinoma in situ (CIS), survival, urothelial cancer
the urinary bladder. Radical cystectomy (RC) remains an important therapeutic strategy in this scenario [4]. Due to its infrequent occurrence, only few reports exist on the outcome of patients after RC for either clinical (cCIS) or pathological (pCIS) CIS only. However, all such studies are substantially limited by including patients with tumour stages ≥T1 before or after RC and consecutively results do not reflect the outcome of an exclusive CIS only series [5–8]. We therefore evaluated the outcome of patients after RC for cCIS (+/− cTa) with no previous history of ≥cT1 disease in TURB specimens and exclusively pTIS in the RC specimens.
Patients and Methods The Institutional Review Board-approved cystectomy database comprises details of all patients who underwent RC at the
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Zehnder et al.
University of Southern California (USC). From 1971 to 2008, RC including extended pelvic lymph node dissection up to the inferior mesenteric artery was performed with curative intent on 1964 patients for urothelial cancer of the bladder. RC specimens were examined using multiple sections from the tumour, bladder wall and mucosa adjacent to and distant from the tumour. Additionally, resected seminal vesicles and prostate specimens in men, and ovaries, uterus and vagina in women were examined. Histological tumour sections for these patients were reviewed by the USC Institute of Pathology. Treatment policy for patients with concomitant urethral CIS consisted of synchronous urethrectomy in the past. More recently (after the year 2000), patients with urethral CIS were primarily observed after RC and selective urethrectomy only performed if urethral recurrence occurred during follow-up. The present study includes patients with preoperative clinical stage cCIS (+/− cTa) but postoperative pathological pCIS-only disease. Any patients with previous history of lamina propria invasion (≥T1) or upper urinary tract tumours were excluded. Of the 1964 patients, 52 met the inclusion criteria, and all operative reports and pathological evaluations were available. Follow-up was routinely performed at 4-month intervals for the first year, semi-annually for the second year and annually thereafter, and consisted of physical examination, voided urine cytology and blood tests. Radiographic evaluation of the upper urinary tract and urinary diversion as well as chest radiography was performed 4 months postoperatively, semi-annually for the second year and annually thereafter. CT of the chest, abdomen and pelvis as well as bone scans were performed when clinically indicated. Bladder cancer recurrence was primarily classified as within or outside the urinary tract. Recurrence within the urinary tract was further stratified according to time point as synchronous or metachronous disease. Recurrence outside the urinary tract was further stratified according to site as local (within the soft tissue field of exenteration and pelvis) and distant (metastatic recurrence outside the pelvis) disease. Clinical outcomes of interest included recurrence-free (RFS; defined as time from RC to first documented clinical recurrence, with patients without recurrence being censored at last follow-up) and overall survival (OS; defined as time from RC to death, with surviving patients being censored at last follow-up). Kaplan–Meier plots were used to estimate the probabilities of RFS and OS for every year since RC.
Results The median (range) age of the 52 patients at RC was 66 (39–87) years. Males comprised 92% of the patient cohort. The number of TURBs per patient before RC ranged from 1 to 11 interventions. Histological evaluation of the TURB-specimen before RC revealed cCIS in 34 (65%) patients and cCIS + cTa tumours in 18 (35%) patients, respectively; 37 (71%)
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patients received intravesical instillations. BCG was used predominantly as a first- and second-line agent. Alternatively, thiopenta, mitomycin C, adriamycin or interferon were applied. In all, 21 patients underwent a single intravesical instillation series. Of the other 16 patients, six received two instillation series, eight patients three series and two patients four and five series each. Of the 13 (25%) patients who underwent immediate RC upon diagnosis, 11 patients had cCIS and two cCIS + extensive Ta disease in the TURB specimen. Four patients with concomitant urethral CIS underwent RC with synchronous urethrectomy. In all, 35 patients (67%) underwent orthotopic diversions, 10 patients (19%) underwent continent cutaneous diversions and seven patients (14%) received ileal conduits (Table 1). Pathological Characteristics of RC Specimens All intraoperative frozen ureteric sections were negative. Pathological review of the RC specimens revealed exclusively pCIS in all patients. Multifocal disease was seen in most (71%) of the bladder specimens. The median (range) lymph node yield was 36 (10–95). None of the patients had lymph node involvement (Table 1). Follow Up, Recurrence and Survival The median (range) follow-up was 8.5 (0.008–34.1) years. One patient died three days after RC from a myocardial infarction. Table 1 The patients' characteristics. Variable Number of patients Median (range) age at surgery, years N (%) aged >65 years N (%): Males Females Number of TURBs before RC: 1 2 3 4 5 6 7, 8, 9, 10, 11 (one patient each) Patients with intravesical instillations before RC Clinical tumour stage before RC: CIS CIS and Ta Pathological features after RC: Tumour stage pCIS Unifocal disease Multifocal disease Tumour positive lymph nodes Median (range) number of identified lymph nodes/patient Urinary diversion, n (%) Orthotopic bladder substitute Catheterizable pouch Ileal conduit
Value 52 66 (39–87) 30 (58) 48 (92) 4 (8) 13 (25) 10 (19) 12 (23) 6 (11) 4 (8) 3 (6) 4 (8) 37 (71) 34 (65) 18 (35) 52 (100) 15 (29) 37 (71) 0 36 (10–95) 35 (67) 10 (19) 7 (14)
Outcome in patients with exclusive CIS after radical cystectomy
Estimated RFS rates at 5 and 10 years were 94% and 90%, respectively. The median OS was 17.2 (0.1–34.1) years with estimated OS rates of 85% and 66% at 5 and 10 years, respectively (Figs 1,2). Further outcome analysis according to preoperative clinical tumour stage cCIS vs cCIS + cTa did not show significant survival difference (5-year RFS: cCIS 90% vs cCIS + cTa 93%, P = 0.51; 5-year OS: cCIS 87% vs cCIS + cTa 75%, P = 0.46).
Fig. 1 RFS, at 5 years 94% and at 10 years 90%.
Estimated Probability of RFS
1.00
0.80
0.60
Disease recurred in four (8%) patients after a median (range) interval of 2.4 (0.5–7.1) years and three of them died (Table 2). Two patients had metachronous recurrence within the urinary tract. More specifically, patient number one had stepwise multifocal urothelial involvement. First, he was diagnosed a distal urethral CIS recurrence 1 year after RC, which was initially managed by a partial urethrectomy, followed by another recurrence of CIS in the proximal urethra resulting in a total urethrectomy. Almost 4 years later, the patient required unilateral nephroureterectomy because of locally advanced upper urinary tract recurrence (pT3 N2), and finally died from the disease 5.3 years after RC. Patient number two was diagnosed with metachronous bilateral upper tract recurrence 7 years after RC and underwent unilateral nephroureterectomy (pT1G3) and contralateral endoscopic tumour ablation (laser) plus mitomycin C instillations; this patient has been disease-free for 12 years.
0.40
0.20 0.00 0
10
20 Years Since Surgery
30
40
Fig. 2 OS, at 5 years 85% and at 10 years 66%.
Estimated Probability of OS
1.00
0.80
0.60
The other two patients recurred outside the urinary tract. Patient number three died of early systemic progression with initially numerous bone metastases 6 months after RC and consecutively retroperitoneal, liver and lung involvement. The fourth patient was diagnosed with a local recurrence in the vaginal vault 3.8 years after RC, received chemotherapy before she finally died 5 years after RC. None of the four patients who underwent RC with synchronous urethrectomy for concomitant urethral CIS recurred.
0.40
0.20
0.00
0
10
20 Years Since Surgery
30
40
Table 2 Characteristics of the four patients with recurrence. Characteristic
Patient number 1
No. of TURBs before RC Intravesical instillations before RC Time to first recurrence, years Site of recurrence
Therapy for recurrence
Development
3 2 courses BCG (12x) 0.99 a. distal urethra b. proximal urethra c. left upper urinary tract a. partial urethrectomy (CIS) b. total urethrectomy (CIS) c. nephroureterectomy left (4 years after RC, pT3N2) Dead from disease (5.3 years after RC)
2 11 1 course BCG (6x) 1 course MMC (6x) 7.1 upper urinary tract
3
4
5 1 course BCG (6x)
2 2 courses BCG (12x)
0.53 vertebra L2-L5 + pelvis
3.8 vaginal vault
Left: nephroureterectomy (pT1G3) Right: ureterorenoscopic laser ablation and 1 course MMC (6x)
None
radio-chemotherapy
disease free (>12 years after RC)
Dead from disease (80% of patients, potentially avoiding the need for urethrectomy and consequent sacrifice of the bladder substitute [17]. This underscores the value of a close urethral follow-up in all patients with a remaining urethra after RC. As most recurrences were diagnosed by symptoms [18], clinicians have to be vigilant in terms of actively looking for new symptoms that would suggest urethral recurrence. The second patient developed bilateral metachronous urothelial cancer in the upper urinary tract 7.1 year after RC. While locally
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advanced upper tract tumours require nephroureterectomy, superficial tumours may be treated with interventions, i.e. laser ablation and immunotherapy [19]. This patient underwent both treatment methods and is currently disease-free with preservation of one kidney and no need for dialysis. The presence of CIS, cancer invading the urethra, positive ureteric and urethral margins, multiplicity of tumours, and a history of recurrent bladder cancer are potential risk factors for upper urinary tract recurrence and emphasise the need for a careful examination of the upper tract before and after RC also when performed for CIS exclusively [20]. The remarkably long time to recurrence in this particular patient suggests the necessity of a life-long follow-up. Two patients were diagnosed with metastatic disease outside the urinary tract. There was an early systemic spread in one patient resulting in death after 6 months. The other patient was found to have local recurrence after nearly 4 years. She first underwent two cycles of palliative chemotherapy with gemcitabine/cisplatin before switching to a second-line regime with four cycles of ifosfamide, taxol and cisplatin due to distant progression. Shortly thereafter bone metastases were diagnosed for which she underwent radiotherapy before she finally died 5 years after RC. While pathological tumour stage, hydronephrosis and number of total lymph nodes identified are independent risk factors for local and distant recurrence after RC for muscle-invasive bladder cancer [21,22], no such parameters have been identified for patients after RC performed for CIS-only disease. Potentially the number of TURBs could increase the risk of recurrence, as each resection bears an inherent risk for perforation [23,24] and for an eventual tumour cell seeding due to TURB under high pressure irrigation. Moreover, tumour cell spillage during RC could be another source; however, our limited cohort does not allow such analyses. CIS in the urinary tract reflects a challenging neoplastic entity for urologists. In view of the potentially life-threatening but also curable course of disease, all patients with CIS require meticulous investigation of the entire urinary tract. Even after identification of CIS inside the urinary bladder, all other potential extravesical sites should be examined, as unidentified CIS in the urethra, prostatic stroma or upper urinary tract may lead to recurrent disease. Serial imaging including the upper urinary tract, voided urine cytology, selective upper urinary tract cytology if indicated, staged TURP and paracollicular biopsies should be performed not only before RC, but also in patients with primary recurrent CIS in the bladder after BCG therapy to exclude extravesical CIS as best as possible. Similarly, extended lifelong follow-up with physical examination, voided urine cytology and urethral barbotage cytology, as well as radiographic control examination of the upper urinary tract and serial imaging are mandatory not only after RC for muscle-invasive cancer but also when performed for CIS exclusively disease.
Outcome in patients with exclusive CIS after radical cystectomy
There are several limitations to our retrospective and single institution study: the few recurrences in the present limited cohort do not allow for extensive statistical analysis. Different urologists performed the TURBs and intravesical installation therapies, therefore consistent reporting of methodology and complications (for example perforation) were not always available, although all operative protocols and pathological reports were reviewed. Moreover, individual treatment histories of the 52 patients before RC were heterogeneous: different numbers of TURBs and/or instillation agents/cycles and different strategies (RC immediately after diagnosis vs RC after BCG failure) represent potential factors that may have influenced outcomes. Nevertheless, we think that the present large single centre series of an exclusive patient cohort with long-term follow-up provides valuable information for urologists in their clinical decision-making. In conclusion, we noted excellent outcomes for patients who underwent RC for exclusively CIS-only disease of the urinary bladder. However, patients may have subclinical synchronous and/or develop metachronous tumours, as well as local and/or distant/systemic recurrence that can be cured but may also occasionally lead to fatal outcomes. Therefore a detailed surveillance of the entire urinary tract after RC for CIS exclusively is of utmost importance.
Conflict of Interest None declared.
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Correspondence: Pascal Zehnder, Department of Urology, University Hospital of Bern, Inselspital 3010 Bern, Switzerland. e-mail:
[email protected] Abbreviations: CIS, carcinoma in situ; OS, overall survival; RC, radical cystectomy; RFS, recurrence-free survival; TURB, transurethral bladder resection; USC, University of Southern California.
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