2012-2013

..... 2012-2013

1 2012-2013 MIBC

(Neoadjuvant chemotherapy)

2

3 1,42 1,10 - 1.39

Increased rates of secondary bladder malignancies have been reported after external-beam radiotherapy(EBRT) for gynaecological malignancies, with relative risks of 2-4 (15). A recent population cohort studyidentified 243,082 men treated for prostate cancer between 1988 and 2003 in the Surveillance, Epidemiologyand End Results database (SEER) in the USA. The standardised incidence ratios for bladder cancer developingafter radical prostatectomy (RP), EBRT, brachytherapy (BT), and EBRT-BT were 0.99, 1.42, 1.10, and 1.39,respectively, in comparison with the general U.S. population. The increased risk of bladder cancer in patientsundergoing ERBT, BT, or ERBT-BT should be taken into account during follow-up, although the likelihoodof mortality was described as very low in a recent study (16). It has recently been proposed that patientswho have received radiotherapy for prostate cancer with modern modalities such as intensity-modulatedradiotherapy (IMRT) may have lower rates of in-field bladder and rectal secondary malignancies (17).Nevertheless, since longer follow-up data are not yet available, and as bladder cancer requires a long periodto develop, patients treated with radiation and with a long life-expectancy are at highest risk and should befollowed up closely (17).4Zelefsky MJ, Housman DM, Pei X, et al. Incidence of secondary cancer development after high-dose intensity-modulated radiotherapy and image-guided brachytherapy for the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):953-9.

:

(IMRT) -In contrast to other studies, we report low rates of IF bladder and rectal SM risks after prostate cancer RT using modern sophisticated treatment techniques. For EBRT patients, compared with the general population, we noted an increased excess risk of OOF skin cancers but not for the brachytherapy patients. When SMs developed, they were generally of an early stage, likely owing to early detection, and the incidence of SM-related mortality was low among these patients. This information would be important to guide patients who are weighing the pros and cons of various treatments to manage prostate cancer. Nevertheless, these data are applicable at 10 years after therapy, and longer follow-up is necessary to clarify the risks at 15 and 20 years after therapy. -EBRT patients were treated with IMRT using a five-field coplanar beam arrangement delivered to the prostate and seminal vesicles using 15 MV photons in daily 1.8-Gy fractions. The treatment planning and delivery were as previously described(12). The median EBRT prescribed dose was 81 Gy -5Zelefsky MJ, Housman DM, Pei X, et al. Incidence of secondary cancer development after high-dose intensity-modulated radiotherapy and image-guided brachytherapy for the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):953-9.

IMRT

The 10-year likelihood of SM development was 25% after EBRT and 15% after brachytherapy (p= .02). The corresponding 10-year likelihood for in-field SM development in these groups was 4.9% and 1.6% (p= .24). 6 Mitra AP, Skinner EC, Miranda G, et al. A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. BJU Int 2013 Feb;111(2): 240-8.

2

To categorize patients with clinical stage T2 bladder cancer into risk groups based on their potential for pathological upstaging and eventual oncological outcomes at cystectomy. To pre-emptively identify such patients who will be upstaged and have poor outcomes after cystectomy, aiming to better determine the ideal candidates for neoadjuvant chemotherapy.

-a patient was considered pathologically upstaged at cystectomy if the tumour was staged pT3 and/or nodal metastasis was detected.

When these factors were included in a decision tree model, 70.6% of patients with hydronephrosis experienced upstaging and had the worst outcome (P< 0.001).In patients without hydronephrosis, tumour growth pattern was a second-tier discriminator (P< 0.001); in patients with non-papillary tumours, 71.7% of cases with evidence of deep muscularis propria involvement experienced upstaging compared to 53.8% of cases with no deep muscle involvement (P= 0.012), whereas, among patients with combined papillary and non-papillary features, 33% of cases aged 65 years were upstaged compared to 47% of cases aged >65 years (P= 0.036).The cross-validated decision tree resulted in three risk groups with significantly varying probabilities of recurrence-free and overall survival (both with overallP< 0.001). 7 Mitra AP, Skinner EC, Miranda G, et al. A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. BJU Int 2013 Feb;111(2): 240-8

948 pT2N0M0

/ pT3

a patient was considered pathologically upstaged at cystectomy if the tumour was staged pT3 and/or nodal metastasis was detected.

8 Mitra AP, Skinner EC, Miranda G, et al. A precystectomy decision model to predict pathological upstaging and oncological outcomes in clinical stage T2 bladder cancer. BJU Int 2013 Feb;111(2): 240-8

:54% : (70,6%) ( ) ( 65 )

A total of 948 patients met the inclusion criteria, of whom 512 (54%) patients were upstaged at cystectomy; upstaging was associated with a worse recurrence-free and overall survival (bothP< 0.001).Age, presence of hydronephrosis, evidence of deep muscularis propria invasion and lymphovascular invasion on transurethral resection specimen, as well as tumour growth pattern and count, were significantly associated with upstaging.When these factors were included in a decision tree model, 70.6% of patients with hydronephrosis experienced upstaging and had the worst outcome (P< 0.001).In patients without hydronephrosis, tumour growth pattern was a second-tier discriminator (P< 0.001); in patients with non-papillary tumours, 71.7% of cases with evidence of deep muscularis propria involvement experienced upstaging compared to 53.8% of cases with no deep muscle involvement (P= 0.012), whereas, among patients with combined papillary and non-papillary features, 33% of cases aged 65 years were upstaged compared to 47% of cases aged >65 years (P= 0.036).The cross-validated decision tree resulted in three risk groups with significantly varying probabilities of recurrence-free and overall survival (both with overallP< 0.001).

9

Nodes 13 comprised the lowmoderate risk group, where 47.5% of patients were upstaged with 5-year RFS and OS probabilities of 66% and 48%, respectively (Table3). Nodes 4 and 5 comprised the moderatehigh risk group, where 54.8% of patients experienced upstaging with 5-year RFS and OS probabilities of 61% and 34%, respectively. Patients in node 6 comprised the high-risk group, where 5-year RFS and OS probabilities of 46% and 27%, respectively, were the lowest, and 70.6% of patients were upstaged. Patients in these risk groups therefore had significantly different RFS and OS (both with overallP< 0.001; Fig.3and Table3). The mean (se) accuracy of the final model in predicting pathological upstaging was 65.7% 10

Nodes 13 comprised the lowmoderate risk group, where 47.5% of patients were upstaged with 5-year RFS and OS probabilities of 66% and 48%, respectively (Table3). Nodes 4 and 5 comprised the moderatehigh risk group, where 54.8% of patients experienced upstaging with 5-year RFS and OS probabilities of 61% and 34%, respectively. Patients in node 6 comprised the high-risk group, where 5-year RFS and OS probabilities of 46% and 27%, respectively, were the lowest, and 70.6% of patients were upstaged. Patients in these risk groups therefore had significantly different RFS and OS (both with overallP< 0.001; Fig.3and Table3). The mean (se) accuracy of the final model in predicting pathological upstaging was 65.7% 11 Lu YY, Chen JH, Liang JA, et al. Clinical value of FDG PET or PET/CT in urinary bladder cancer: a systemic review and meta-analysis. Eur J Radiol 2012 Sep;81(9):2411-6.

FDG PET PET/CT

H Fruorodeoxyglucose (FDG):

FDG PET

-a meta-analysis of pooled sensitivity and specificity in detecting primary and metastatic lesions of bladder cancer

Fludeoxyglucose: heart, lungs, brain tumors

The pooled sensitivity and specificity of PET/CT for primary lesion detection of bladder cancer were 0.90 (95% CI: 0.700.99) and 1.00 (95% CI: 0.741.00), respectively. The pooled sensitivity and specificity of FDG PET or PET/CT for staging or restaging (metastatic lesions) of bladder cancer were 0.82 (95% CI: 0.720.89) and 0.89 (95% CI: 0.810.95), respectively.

The diagnostic accuracy of FDG PET or PET/CT is good in metastatic lesions of urinary bladder cancer. Due to the small number of patients and limited number of studies analyzed, the diagnostic capability of FDG PET or PET/CT in detection of primary bladder wall lesions could not be assessed 12 Lu YY, Chen JH, Liang JA, et al. Clinical value of FDG PET or PET/CT in urinary bladder cancer: a systemic review and meta-analysis. Eur J Radiol 2012 Sep;81(9):2411-6. 0.90 1.00: (2) ( ) 0.82 0.89

- ? ? 0.90 (95% CI: 0.700.99) 1.00 (95% CI: 0.741.00): (2)

( ) 0.82 (95% CI: 0.720.89) 0.89 (95% CI: 0.810.95) 13 Vargas HA, Akin O, Schder H, et al. Prospective evaluation of MRI, C-acetate PET/CT and contrast enhanced CT for staging of bladder cancer. Eur J Radiol 2012 Dec;81(12):4131-7. MRI, CT C-acetate PET/CT

The exact uptake mechanism of 11C-acetate is not known, but studies suggest that it is incorporated into the lipid pool in cancer tissue with low oxidative metabolism and high lipid synthesis.

In staging bladder cancer, MRI,11C-acetate PET/CT and CT displayed similar levels of accuracy. For all modalities, a history of intravesical and/or systemic chemotherapy affected staging accuracy

Unfortunately, we found that for all three imaging modalities studied, staging accuracy was negatively affected by prior BCG administration.11C-acetate PET/CT appeared to be most affected, having the lowest specificity of all 3 modalities for detection of nodal metastases in patients with prior intravesical BCG administration ( . 14

15 Vargas HA, Akin O, Schder H, et al. Prospective evaluation of MRI, C-acetate PET/CT and contrast enhanced CT for staging of bladder cancer. Eur J Radiol 2012 Dec;81(12):4131-7.

MRI: 56% 38% 6% CT: 63% 31% 6% C-acetate PET/CT (9 ) 7 2MRI correctly staged 56% (9/16) of patients, overstaged 38% (6/16) and understaged 6% (1/16). CT correctly staged 63% (10/16) of patients, overstaged 31% (5/16) and understaged 6% (1/16). T stages determined at pathology, MRI and CT are summarized inTable 2. On11C-acetate PET/CT, there was uptake within the bladder wall in 9 patients; the uptake was true positive in 7 and false positive in 2 patients. In the 7 patients without11C-acetate uptake in the bladder wall, the results were true negative in 5 and false negative in 2. An example of a patient who was correctly staged with MRI and CT and had true-positive uptake on PET is shown inFig. 2. 16 Vargas HA, Akin O, Schder H, et al. Prospective evaluation of MRI, C-acetate PET/CT and contrast enhanced CT for staging of bladder cancer. Eur J Radiol 2012 Dec;81(12):4131-7. BCG43% CT MRI

BCG67% MRI78% CT

Both MRI and CT correctly staged 43% (3/7) of patients who had received intravesical BCG prior to imaging. Among patients with no history of intravesical BCG therapy, the percentage correctly staged increased to 67% (6/9) for MRI and 78% (7/9) for CT. 17 MRI CT BCG

18 Vargas HA, Akin O, Schder H, et al. Prospective evaluation of MRI, C-acetate PET/CT and contrast enhanced CT for staging of bladder cancer. Eur J Radiol 2012 Dec;81(12):4131-7. 44% MRI67% CT 71% MRI57% CT

Of the 9 patients who had received systemic chemotherapy prior to imaging, MRI and CT correctly staged 44% (4/9) and 67% (6/9) and overstaged 44% (4/9) and 33% (3/9), respectively. Of the patients who had not received systemic chemotherapy before imaging, MRI and CT correctly staged 71% (5/7) and 57% (4/7) and overstaged 29% (2/7) and 43% (3/7), respectively. The only patient who was understaged on both MRI and CT received systemic chemotherapy before imaging. 19 Vargas HA, Akin O, Schder H, et al. Prospective evaluation of MRI, C-acetate PET/CT and contrast enhanced CT for staging of bladder cancer. Eur J Radiol 2012 Dec;81(12):4131-7.

BCG() 20 Yoshida S, Koga F, Kobayashi S, et al. Role of diffusion-weighted magnetic resonance imaging in predicting sensitivity to chemoradiotherapy in muscle-invasive bladder cancer. IntJRadiat OncolBiol Phys2012May1;83(1):e21-7

(DW MRI) -

- In chemoradiation (CRT)-based bladder-sparing approaches for muscle invasive bladder cancer (MIBC), patients who respond favorably to induction CRT enjoy the benefits of bladder preservation, whereas nonresponders do not. Thus, accurate prediction of CRT sensitivity would optimize patient selection for bladder-sparing protocols. Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that quantifies the diffusion of water molecules in a noninvasive manner. We investigated whether DW-MRI predicts CRT sensitivity of MIBC. 21 Yoshida S, Koga F, Kobayashi S, et al. Role of diffusion-weighted magnetic resonance imaging in predicting sensitivity to chemoradiotherapy in muscle-invasive bladder cancer. IntJRadiat OncolBiol Phys2012May1;83(1):e21-7

H

(ADC)

23 MIBC patients (cT2/T3= 7/16) who underwent induction CRT consisting of radiotherapy to the small pelvis (40 Gy) with two cycles of cisplatin (20 mg/day for 5 days), followed by partial or radical cystectomy. All patients underwent DW-MRI before the initiation of treatment. Associations of apparent diffusion coefficient (ADC) values with CRT sensitivity were analyzed. The proliferative potential of MIBC was also assessed by analyzing the Ki-67 labeling index (LI) in pretherapeutic biopsy specimens.

The current study, for the first time to our knowledge, demonstrates the role of DW-MRI in predicting CRT sensitivity of MIBC. Patients with MIBC who have lower ADC values are likely to have a favorable response to induction CRT and thus enjoy its potential benefit, including improved quality of life with bladder preservation and improved survival(14). DW-MRI potentially contributes to optimized patient selection for CRT-based bladder-sparing approaches in a simple and noninvasive manner 22

23 Yoshida S, Koga F, Kobayashi S, et al. Role of diffusion-weighted magnetic resonance imaging in predicting sensitivity to chemoradiotherapy in muscle-invasive bladder cancer. IntJRadiat OncolBiol Phys2012May1;83(1):e21-7

23 cT2-3 DW-MRI

The study cohort consisted of 23 MIBC patients (cT2/T3= 7/16) who underwent induction CRT consisting of radiotherapy to the small pelvis (40 Gy) with two cycles of cisplatin (20 mg/day for 5 days), followed by partial or radical cystectomy. All patients underwent DW-MRI before the initiation of treatment. Associations of apparent diffusion coefficient (ADC) values with CRT sensitivity were analyzed. The proliferative potential of MIBC was also assessed by analyzing the Ki-67 labeling index (LI) in pretherapeutic biopsy specimens. 24 Yoshida S, Koga F, Kobayashi S, et al. Role of diffusion-weighted magnetic resonance imaging in predicting sensitivity to chemoradiotherapy in muscle-invasive bladder cancer. IntJRadiat OncolBiol Phys2012May1;83(1):e21-7

-

ADC - (p50% died because of systemic diseas Reported independent predictors of urethral recurrence were cystectomy for NMIBC, prostate involvement, and a history of previously recurrent NMIBC

The surveillance strategies range from observation alone to monitoring with cytology by urethral washings and urethroscopy. In several studies, there was no reported significant survival difference in patients followed with or without urethral washings[78]. However, a recent large retrospective series reported a highly significant survival advantage in male patients with urethral recurrence diagnosed asymptomatic by follow-up compared with male patients diagnosed by symptoms (LE 3)[83]. Thus, follow-up of the male urethra should be recommended, and any pertaining symptoms must be investigated. Recurrent CIS in the urethra with orthotopic bladder substitution can be treated successfully with intraurethral BCG in approximately 80% of patients, while papillary and invasive urethral recurrence should lead to urethrectomy[78]. Fewer data are available on the treatment of urethral recurrences in females. All reported cases were treated with urethrectomy[80],[81]and[82].

38Follow up 1,8-6%

(28-49 ) 10-55

20cm, B12serum levels should be measured. Vitamin B12deficiency may lead to megaloblastic anaemia reversible by substitution treatment and irreversible neuropathy As the average body deposits of vitamin B12are large, vitamin B12measurements and/or substitution should be realised from 35 yr after RC onwards (GR C).

Metabolic acidosis can be expected in 15% of patients with an ileal conduit The risk of metabolic acidosis is the highest during the early postoperative period, in neobladder patients with postvoid residual urine, with urinary tract infection, and in patients with reduced renal function. Serum evaluation for metabolic acidosis should be done regularly during the first 12 mo after RC and then probably every 612 mo (GR C).

The most frequent complications are symptomatic urinary tract infections; urolithiasis; stenosis of the ureterointestinal anastomosis with potential loss of renal function; complications related to the stoma in conduits; and in neobladder patients, urinary retention and day and/or nighttime incontinence. In a series with ileal conduit, complications developed in 45% of patients within the first 5 yr. This percentage increased to 50%, 54%, and 94% in patients surviving 10, 15, and >15 yr, respectively (LE 3)

40Follow up Follow up 45% ileal conduit 5 50% 10 94% >15

The most frequent complications are symptomatic urinary tract infections; urolithiasis; stenosis of the ureterointestinal anastomosis with potential loss of renal function; complications related to the stoma in conduits; and in neobladder patients, urinary retention and day and/or nighttime incontinence. In a series with ileal conduit, complications developed in 45% of patients within the first 5 yr. This percentage increased to 50%, 54%, and 94% in patients surviving 10, 15, and >15 yr, respectively (LE 3)

41Follow up

5

The early detection of tumour recurrence after RC allows for early treatment. As most relapses occur within 5 yr and the median time to local and distant recurrence is 1218 mo after RC, follow-up should be intensive for the first 5 yr, particularly for the first 2 yr. Patients with extravesical and lymph nodpositive disease at RC have the highest risk of recurrence. Regular follow-up of the male urethra by urethral washings and urethroscopy has survival benefit, if urethral recurrence is diagnosed early before symptoms occur. Most upper urinary tract recurrences occur >3 yr after RC, at a time when the risk of local and systemic recurrence is decreasing. Lifelong yearly upper urinary tract imaging is advisable in all patients. This study also allows for early detection of urinary diversion complications. Metabolic evaluation should continue throughout life, and vitamin B12substitution should commence from 35 yr after surgery (Table 8andTable 9). In general, the studies about follow-up after RC are low LE and based on retrospective data. Nonetheless, reasonable recommendations can be made until further prospective randomised studies that test different follow-up schedules have been performed. 42

43