If all investigations are normal, consideration should be given to neph- rological disorder s that may cause haematuria such as glomerulonephritis. Annual monitoring of BP, urinalysis , and eGFR is recommended. Cross- referral to a renal physician is advised in patients with persisting micro- scopic haematuria 9 proteinuria and hypertension or eGFR <60mL/min. Refe rral back for further urological investigation is required if haema- turia becomes visible (CTU indicated) or NVH persists, but becomes symptomatic. Patients with predominantly \201 lling-type LUTS, suprapubic pain, or recurrent UTI/pneumaturia should also have urine cytology and cystoscopy. Causes of persistent NVH Urological causes Common - - - - - - Benign prostatic hyperplasia. Cancer (bladder, kidney, prostate, ureter). Calculus disease or nephrolithiasis. Cystitis or pyelonephritis. Prostatitis or urethritis. Schistosoma haem atobium infection. Less common - - - - - Radiation cystitis. Urethral strictures. TB Medullary sponge kidney. Cyclophosphamide-induc ed cystitis. . Rare - - - - - Arteriovenous malformation. Renal artery thrombosis. Polycystic kidney disease. Papillary n ecrosis of any cause. Loin pain haematuria syndrome. Nephrological causes Common - - IgA nephropathy (Berger \200\231s disease). Thin basement membrane disease. Less common/rare - Acute glomerular disease. \200 \200 \200 \200 \200 Post-infectious glomerulonephritis. Rapidly progressive glomerulonephritis. Systemic lupus nephritis. Vasculitis. Goodpasture \200\231s disease. CHAPTER 7 Urological neoplasia 274 Henoch \200\223Sch nlein purpura syndrome. \200 Haemolytic uraemic syndrome. Chronic pri mary glomerulonephritis. \200 \200 \200 \200 Familial causes. \200 Polycystic kid ney disease (autosomal dominant or recessive). Focal segmental glomerulonephritis. Mesangiocapillary glomerulonephritis Membranous nephrop athy. Mesangial proliferative glomerulonephritis. Hereditary nephritis (Alport \200\231s syndrome). Urine cytology Examination of voided urine for exfoliated cells is most sensitive (90 \200 \223100%) in patients with high-grade TCC and CIS, anywhere in the urinary tract. It is cos tly and <1% of cancers are detected by cytology alone when other investigations are normal. False-negative cytology is frequent (40 \200\22370%) in patients with papillary TCC while false-positive cytology can arise due to infection, in \202 ammation, stones, instrumentat ion, and intravesical instilla- tions such as chemotherapy. Guidelines do not specify if an d when to use it so practices vary. Urine molecular markers ELISA tests for detecting tumor-speci \201 c urinary markers such as bladder tumor antigen (BTA) or nuclear matrix protein 22 (NMP22) tend to have greater se nsitivity, but reduced speci \201 city for detecting TCC, compared with urine cytology. Im munoCyt has the highest sensitivity for detection of low-grade tumors and is less affected by other urological diseases. However, with a 60% detection rate for low-grade tumors, the test remains largely inadequate to replace cystoscopy. The absence of clinical trials and t he costs involved mean that it is unclear whether these tests, alone or in combination, may replace any of the standard investigations for haematuria. Diagnosis and initial treatment of bladder cancer TURBT usually provides de \201 nitive hi stological diagnosis, grade, and clini- cal and pathological stage and is the \201 rst (s ometimes sole) treatment. This is undertaken under general or spinal anesthesia; bimanual e xamination is mandatory before and after bladder tumor resection to assess size, position, and mobility. If possible, the surgeon should resect the tumor(s) completely. The pathologi st should report on the tumor type, grade, and stage; in particular, the presence or absenc e of muscularis propria should be noted since its absence will preclude reliable T staging. Red areas are biopsied separately; the prostatic urethra is biopsied if cystectomy with bl adder reconstruction is under consideration. Particular care is taken when resecting tumors at the dome since intraperitoneal bladder per- foration may occur, especially in women wit h thin-walled bladders. Care is also taken when resecting posterolateral tumors due to the proximity of the obturator nerve; stimulation may result in a \200\230kick \200\231 unless the patient is under full paralysis, which may lead to bladder perforation and/or trou- bl esome bleeding. BLADDER CANCER: HAEMATURIA, DIAGNOSIS, AND TURBT 275 Narrow-band imaging (NBI) and photodynamic detection (PDD) - : is an optical image enhancement technology in which the narrow NBI bandwidth of light is strongly absorbed by hemoglobin and penetrates only the surface of tissue, increasing the v isibility of capillaries and other delicate tissue surface structures by enhancing contrast between the two. A number of small studies have demonstrated NBI to be superior to standar d white light cystoscopy for the detection of new and recurrent tumors. PDD a porphyrin-bas ed photosensitizer, hexaminolevulinic acid (HAL; Hexvix ). Several randomized studies have revealed CIS lesions and developing papillary tumors which cannot be seen using standard w hite light for tumor detection and resection. For example, a total of 113 CIS lesions in 58 patients 104 (92%) were detected by PDD, 77 (68%) were detected by white light cystoscopy, while 5 were detected only by biopsy of visually normal mucosa.2 The 1y risk of papillary recurrence is reduced by 9 \200\22327% This technique is gaining popularity, but is expensi ve; however, it has been suggested that improved tumor detection leads to better patient ma nagement and reduced long-term recurrence rates and costs. The value of PDD for improvement of the outcome in relation to progression rate or survival remains to be demonstrated, tho ugh it has gained a place in routine management of selected patients, particularly in those with positive urine cytology, but normal-looking bladder mucosa. ( \202 uorescence cystocopy): uses blue light in combination with Staging investigations are usually reserved for patients with biopsy-proven muscle-invasive bladder cancer unless clinically indicated since non-mus- cle-invasive TCC and CIS are rar ely associated with metastases. 1 Kelly JD, Fawcett DP, Goldberg LC (2009) Assessment and management of non-visible haema- turia in primary care. BMJ 338:a3021. 2 Fradet Y, Grossman HB, Gomella L, et al. (2007) A comparison of hexaminolevulinate \202 uores- cence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. J Urol 178:68 \200\22373. CHAPTER 7 Urological neoplasia 276 Bladder cancer (non-muscle invasive TCC): surgery and recurrence TURBT The diagnostic role of TURBT has been discussed on b p. 274. As a primary treatment, a visually complete tumor resection is adequate for 70% of newly presenting patients with Ta/T1 super \201 cial dise ase. The re- maining 30% of patients experience early recurrence, 15% with upstaging. Becau se of this, it is standard care that all new patients receive adjuvant treatment with a sin gle dose of post-operative intravesical chemotherapy (usually mitomycin; see b p. 280). Com plications of TURBT are uncom- mon, including bleeding, sepsis, bladder perforation, incomp lete resection, and urethral stricture. Alternatives to TURBT Transurethral cystodiathermy or laser are accepted, quicker and less mor- bid procedure for ablating small super \201 cial recurrences when obtaining tissue fo r histology is not considered necessary. Fluorescence and NBI cystocopy are discussed on b p. 275. Follow-up after TURBT Second resection: an early repeat TUR (within 2 \200\2236 weeks) shou ld be undertaken: (a) if the \201 rst resection was incomplete, (b) when the pathologist reports that the resected specimen contains no muscu- laris propria, or (c) if a high-grade , but apparently non-invasive, T1 tumor has been reported since perhaps 10% (3 \200\22325%) of these G3pT1 tumors are understaged T2 tumors. This strategy improves recur- rence-free survival and prognosis while complications include bladder perforation. In the absence of these indications for a second resection, review cys- toscopy is performe d at 3 months. If this demonstrates recurrence, 70% will recur further. If not, only 20% wi ll recur further. If the bladder is clear at follow-up, subsequent cystoscopies are perform ed under local anaes- thetic at 9 months and thereafter annually for 5y (patients with low- risk TCC) or until the patient is no longer \201 t to undergo treatment (patients with hi gh-risk disease). Patients with G3T1 TCC, and CIS are at signi \201 cantly higher risk of recurrence and 40% subsequently upstage. Some patients experience per- sistent symptomatic multifocal G1/2, T a/1 recurrent TCC, demanding fre- quent follow-up procedures. In these circumstances, adjuv ant treatment is indicated (see b p. 280). There is no accepted protocol for upper tract surveillance in patients with a history of bl adder TCC, although EAU guidelines1 recommend yearly imaging (CTU) for patients with high-r isk disease. BLADDER CANCER: SURGERY AND RECURRENCE 277 Predicting recurrence and progression in Ta/T1 TCC A validated scoring system based on the following factors has been devel- oped (by the EORTC):2 - - - - - - Number of tumors (e.g. 1 = 0 points; 2 \200\2237 = 3 points; Tumor diameter (<3cm vs >3cm). Prior recurrence <1 vs >1 per year). T stage (Ta vs T1). Tumor grade (G1 vs G2 vs G3). Pre sence of concomitant (cid:116)8 = 6 points). CIS. This system divides super \201 cial tumors into those at low risk (50%), in- termediate ri sk (35%), or high risk (15%) of recurrence and progression at 1y or 5y. The scoring tables and risk calculators are available at: M http:// www.eortc.be/tools/bladdercalculator/. See Table 7.10 for a summary of the management of bladder cancer by grade and stage. 2 7 8 Table 7.10 A summary of the management of bladder cancer C H A P T E R 7 Histology Risk of recurrence post-TURBT Risk of stage progression Further treatment Urological follow-up U r o l o g i c a l G1/2, Ta/1, TCC 30% 10 \200\22315% Immediate post-operative single dose intravesical chemotherapy Review cystoscopies, commencing 3 months Recurrent multifocal G1/2, Ta/1 TCC 70%+ 10 \200\22315% Intravesical chemotherapy x 6 weekly doses Review cystoscopies, commencing 3 months G3, Ta/T1 TCC 80% 40% Second resection; intravesical BCG x 6 weekly doses; consider cystectomy for recurrence Review cystoscopies, commencing 6 \200\22312 weeks n e o p l a s i a CIS (carcinoma in situ, severe intraepithelial dysplasia) 80% 40% Intravesical BCG x 6 weekly doses 9 maintenance; consider cystectomy for recurrence Cystoscopies + biopsy and cytology commencing 3 months pT2/3, N0, M0 TCC, SCC or adenocarcinoma Usually TUR is incomplete N/a Cystectomy or radiotherapy 9 neoadjuvant chemotherapy or palliative TURBT (un \201 t) Cystoscopies if bladder is preserved. Urethral washings for cytology. T4 or metastatic TCC, SCC, or adenocarcinoma Usually TUR is incomplete N/a Systemic chemotherapy; multidisciplinary team symptom palliation Palliative treatment for local bladder symptoms BLADDER CANCER: SURGERY AND RECURRENCE 279 1 European Association of Urology Guidelines on Non \200\223Muscle-Invasive Urothelial Carc inoma of the Bladder, the 2011 update. Eur Urol 59: 997 \200\2231008. 2 Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. (2006) Predicting recurrence and pro- gression in individual patients with stage Ta T1 bladder cancer using EORTC risk table s: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49: 466 \200\2237 7. CHAPTER 7 Urological neoplasia 280 Bladder cancer (non-muscle invasive TCC): adjuvant treatment Intravesical chemotherapy (e.g . mitomycin C (MMC) 40mg in 50mL sa- line) is used for G1-2, Ta or T1 tumors, and recurrent multifocal TCC. MMC is an antibiotic chemotherapeutic agent that inhibits DNA synthe- sis. In experimental studies, it may cause regression of small papillary TCC so it should be cy totoxic for microscopic residual disease post-TURBT. A meta-analysis of seven randomized tr ials1 demonstrated that a single dose given within 24h of \201 rst TURBT signi \201 cant ly (24%) reduces the like- lihood of tumor recurrence compared to TURBT alone, from 48% to 37%. This is now standard treatment for all new papillary bladder tumors post-TURBT. For many patients at low risk of recurrence, the risk reduction seen with single-dose chemo therapy is equivalent to that seen using weekly instilla- tions for 6 weeks, commencing up to 2 weeks post-TURBT. Such longer courses are still recommended for patients at higher ris k of recurrence or who have multifocal recurrences, excluding those with high-grade Ta/1 TC C or CIS. Intravesical chemotherapy has never been shown to prevent progres- sion to muscle invasion and has no impact upon survival. It is administered via a urethral catheter, is held in the bladder for 1h, and should not be used if there is ongoing haematuria or if bladder perfor ation is suspected. Toxicity of MMC: 15% patients report transient \201 lling-type LUTS; occa- sionally a rash develops on the genitals or palms of the hands so treatment must be s topped. Systemic toxicity is rare with MMC. Other effective intravesical chemotherapy agents include doxorubicin and epirubicin, but not gemcitabine. Intravesical BCG: is an attenuated strain of Mycobacte rium bovis. Commercially available strains include Pasteur, Connaught, and Tice. It acts as an immune stimulant, upregulating cytokines such as IL-6 and IL-8 in the bladder wall, act ivating immune effector cells. BCG produces complete responses in 60 \200\22370% of patients. It is as effec- tive as chem otherapy for adjuvant treatment of low- and intermediate- risk G1/2, Ta/1 TCC, therefore, i s not often used (except as second-line) because of the additional toxicity. In high-risk p atients, with multiple G2T1, high-grade G2 or G3Ta/T1, or CIS, the bene \201 t of BCG over chemotherapy in reducing risk of recurrence is clear and it is standard care. BCG is given as a 6-week induction course, starting at least 2 weeks post-TURBT. It is administered via a urethral catheter, 80mg in 50mL saline and retained in the bladder for 1h. A meta-analysis of 24 trials has demonstrated that BCG reduces risk of stage progression (t o muscle invasion) by 27%, based on a median fol- low-up of 2.5y.2 This effect was only see n in patients who received mainte- nance BCG (e.g. 30 treatments over 3y after the initial 6-week induction), which is now the standard recommendation for high-grade Ta/T1 or CIS ini tial responders, though the optimal dose and schedule remain unclear. For recurrent high-gr ade Ta/T1 or CIS, a second course of BCG may BLADDER CANCER: ADJUVANT TREATMENT 281 be offered if maintenance was not given, as 50% will respond. A total of 66% of BCG non-res ponders and 10 \200\22320% of initial responders will even- tually progress to muscle-invas ive TCC. Hence, if no response is seen or relapse diagnosed despite BCG maintenance or a se cond course, proceed without delay to radical cystectomy; the cure rate is 90%. Though less expensive and more effective, BCG is more toxic than intra- vesical chemotherap y, causing cystitis symptoms in >90% patients and low- grade fever with myalgia in 25%. Up to 6% of patients develop a high persistent fever, requiring antituberculous therapy for 6 months with iso- niazid and pyridoxine or standard triple therapy (rifampicin, isoniazid, a nd ethambutol) in critically ill patients. Death due to BCG sepsis, granuloma- tous prostat itis, and epididymo-orchitis are rare complications. Contraindications to intravesical BCG include: Immunosuppressed patients. Pregnant or lacta ting women. Patients with hematological malignancy. Following traumatic catheterization. - - The appearances at cystoscopy performed too soon after BCG can ap- pear alarming due to a g eneralized in \202 ammatory response. Cystoscopy and biopsy 3 months after BCG may still r eveal chronic granulomatous in \202 ammation. 1 Sylvester RJ, Oosterlinck W, van der Meijden AP (2004) A single immediate postoperative i nstillation of chemotherapy decreases the risk of recurrence in patients with stage TaT1 bl adder cancer: a meta-analysis. J Urol 171:2186 \200\22390. 2 Sylvester RJ, van der Meijden AP, Lamm DL (2002) Intravesical BCG reduces the risk of pro - gression in patients with super \201 cial baldder cancer: a combined analysis of results of published clinical trials. J Urol 168:1964 \200\22370. CHAPTER 7 Urological neoplasia 282 Bladder cancer (muscle-invasive): staging and surgical management of localized (pT2/3a) dis ease This is a dangerous disease; the untreated 5y survival is just 3%. Management of patie nts with invasive bladder cancer requires a multidisciplinary team approach, involving case -by-case discussion between the urological sur- geon, radiotherapist, and medical oncologis t, with support from the pa- thologist, radiologist, and cancer specialist nurse. Staging investigations - Pelvic CT or MRI: may demonstrate extravesical tumor extension, upper tract obstruction, or iliac lymphadenopathy reported if >8mm in maximal diameter. T stage correlation with patho logical \201 ndings at cystectomy is 65 \200\22380%. Both modalities will miss microscopi c nodal disease in 70% of cases. Chest Isotope bone scan TCC): is obtained in cases being c onsidered for radical treatment. Ultrasound scanning serum liver function is abnormal; albu min indicates the nutritional status of the patients; alkaline phosphatase is not a reliabl e marker for bone disease in bladder cancer patients. CT or plain X-ray. (positive in 5 \200\22315% of patients with muscle-invasive : is used for detection of liver metastases if the In the absence of prospective randomized trials comparing the surgical and non-surgical tre atments, the options for a patient with newly diagnosed con \201 ned muscle-invasive bladd er cancer are: - Bladder preserving. \200 Radical mainstream. Palliative patients. 9 neoadjuvant systemic chemotherapy. Partial cyste ctomy plus de \201 nitive RT (see b p. 286): poor options for TURBT squamous and adenocarc inoma as they are seldom radiosensitive. TURBT plus systemic chemotherapy: little data, not TURBT 9 palliative radiotherapy (RT): for elderly/un \201 t \200 Radical cystectomy with: \200 \200 \200 \200 9 Neoadjuvant chemotherapy: some evide nce of bene \201 t (see b Ileal conduit urinary diversion. Ureterosigmoidostomy urinary diversion. Continent urinary diversion. p. 286). 9 Neoadjuvant RT: no evidence of bene \201 t (see b p. 288). Partial cystectomy is a good option for well selected patients with small solitary disease located near the dome and for urachal carcinoma. Morbidity is less than with radical cystec tomy and diversion is not re- quired. The surgical specimen should be covered with perivesi cal fat, with a 1.5cm margin of macroscopically normal bladder around the tumor. There shou ld be no biopsy evidence of CIS elsewhere in the bladder. BLADDER CANCER: STAGING AND SURGICAL MANAGEMENT 283 The bladder must be closed without tension and catheterized for 7 \200\22310 days to allow healing. Subsequent review cystoscopies are mandatory to ensure no tumor recurrence. Radical cystectomy with urinary diversion This is the most effective primary treatment for muscle-invasive TCC, SCC, and adenocarcinoma and can be performed as salvage treatment if R T has failed. It is also a treatment for G3T1 TCC and CIS, refractory to BCG. Any ureteric obstruction caused by the primary tumor will be relieved by the concomitant urinary diversi on. However, this is a major undertaking for the patient and surgeon, requiring support fro m the can- cer specialist nurse, stomatherapist, or continence advisor. Preoperative bowel preparation is discouraged by \200\230enhanced recovery \200\231 specialists since it is c onsidered to cause unnecessary dehydration without any evidence of bene \201 t. The proced ure: through a midline transperitoneal or extraperitoneal ap- proach, a bilateral pelvic ly mphadenectomy is undertaken. The extent of lymphadenectomy ranges from limiting dissection to the obturator fos- sa to extending the dissection up to the aortic bifurcation. Studies have suggested a survival advantage to the extended approach, provided the primary cancer i s stage T2 or less. The \201 ndings of frozen section histology may in \202 uence the de cision to proceed in some cases. The entire bladder is then excised along with perivesical fat, vascular pedicles, and urachus, plus the prostate/seminal vesicles or anterior vaginal wall. The anterior urethra is not excised unless there is prior biopsy evidence of tumor a t the fe- male bladder neck or prostatic urethra (when recurrence occurs in 37%). The urete rs are divided close to the bladder, ensuring their disease-free status by frozen section h istology, if necessary, and anastomosed into the chosen urinary diversion (see b p. 290). Some centers are pioneering laparoscopic and robot-assisted cystectomy. Advantages include less blood loss, less post-operative analgesia require- ment, and reduced hospital stay. Ho wever, long operating times, high cost, and technical considerations may limit widespread a doption of this approach. Oncological outcomes are still under evaluation. Major complicati ons affect 25% of cystectomy patients. These include perioperative death (1.2%), reoperatio n (10%), bleeding, thromboembo- lism, sepsis, wound infection/dehiscence (10%), intestinal obstruction or prolonged ileus (10%), cardiopulmonary morbidity, and rectal injury (4%). Er ectile dysfunction is likely after cystectomy due to cavernosal nerve injury. The complications of urinary diversion are discussed on b p. 290. Post-operative care - Many patients will spend the \201 rst 24h in the high dependency unit or ITU. Daily clini cal evaluations, including inspection of the wound (and stoma, if present), \202 uid bala nce, urine and drain outputs, blood count, creatinine/electrolytes, and albumin. Broad-spec trum antimicrobial prophylaxis. CHAPTER 7 Urological neoplasia 284 Venous thromboembolism prophylaxis with calf compression, and subcutaneous LMWH (unfraction ated heparin for patients with renal impairment); NICE (2010) recommends continuing heparin for 28 post-operative days. Early mobilization within 24h, if possible. Chest physiotherap y and adequate analgesia is especially important in smokers and patients with chest comorbi dity. Oral intake is commenced early, an integral part of the Enhanced Recovery concept; ho wever, patients may require parenteral nutrition in the presence of GI complications or pro longed ileus. Drains are usually sited in the pelvis and near the ureterodiversion anastamo sis; ureteric catheters pass from the renal pelves through the diversion and exit percutane ously; a catheter drains the diversion (except in the case of ileal conduit), exiting ureth rally or suprapubically. Most patients stay in hospital for 10 \200\22314 days. TED stockings, pneumatic Salvage radical cystectomy is technically a more dif \201 cult and slightly more morbid pr ocedure. Relatively few patients who have failed primary RT are suitable for this second ch ance of a cure; these are \201 t patients with mobile clinically localized disease. Ef \201 cacy of radical cystectomy Failure to cure may result from inadequate excision of the primary tu- mour or presence of metastases (Table 7.11). Treatment delay should be avoi ded if possible; cystectomy performed within 3 months of diagno- sis (T2 TCC) results in si gni \201 cantly improved survival compared with >3 months.1 Pathological upstaging of the primary can occur in up to 40% of cases. Lymph node metastases occur in 10% of T1 and up to 33% of T3 \200\2234 cancers. The use of neoadjuvant chemotherapy in muscle-invasive diseas e is discussed on b p. 288. Table 7.11 5y survival rates for cystectomy alone Stage T1/CIS 90%+ Stages T2,T3a 55 \200\22363% Stage T3b 31 \200\22340% Stage T4a (into prostate) 10 \200\22325% Stage TxN1 \200\2232 30% Salvage T0 70% Salvage T1 50% Salvage T2, 3a 25% 1 Lee CT, Madii R, Daignault S, et al. (2006) Cystectomy delay more than 3 months from init ial bladder cancer diagnosis results in decreased disease speci \201 c and overall surviva l. J Urol 175:1262 \200\2237. This page intentionally left blank CHAPTER 7 Urological neoplasia 286 Bladder cancer (muscle-invasive): radical radiotherapy and palliative treatment Management of patients with invasive bladder cancer requires a multidisci- plinary team approach, invo lving case-by-case discussion between the uro- logical surgeon, radiotherapist, and medical oncologist, supported by the pathologist, radiologist, and cancer nurse specialist. Radical external beam RT is a good option for pT2 \200\2234 TCC in patients who are un \201 t or unwilling to undergo cystectomy, but who still wish to have the chance of cure. T ypically, a total dose of 66 Gray is administered in 30 fractions over 6 weeks. The target \201 eld comprises the bladder only, with a 1.5cm safety margin to allow for movement. The 5y survival rates at 40 \200\22360%, are inferior to those of cystectomy, but the bladd er is preserved and the complications are less signi \201 cant (Table 7.12). Higher-grade tumors tend to do less well, perhaps because of the undetected presence of disease outside the \201 eld of irradiation. Beyond this, prediction of RT response remains dif \201 cul t, relying on fol- low-up cystoscopy, and biopsy. Local recurrence occurs in approximately 30% of patients. There may be a small bene \201 t in the use of neoadjuvant or adjuvant ci splatin-based combination chemotherapy with RT in locally advanced (pT3b/4) disease (see b p. 288). Interstitial brachytherapy using caesium or iridium sources can be used to treat small T2 T CC in combination with RT and bladder-preserving surgery. Use of this technique is not wide spread. CIS, SCC, and adenocarcinoma are poorly sensitive to RT. There is no advantage in giving precystectomy RT for invasive TCC. Complications occur in 70% of patients, self-limiting in 95% of cases. These include radiat ion cystitis ( \201 lling LUTS and dysuria) and proctitis (diarrhea and rectal bleeding), usually lasting only a few months. Refractory radia- tion cystitis and haematuria may rarel y require desperate measures such as intravesical alum, formalin, hyperbaric oxygen, iliac artery embolization, or even palliative cystectomy. Table 7.12 Ef \201 cacy of RT: 5y survival Stage T1 70% (with adjuvant chemotherapy) Stages T2 40% Stage T3a 35% Stage T3b,T4 10 \200\22320% Stage TxN1 \200\2232 7% RADICAL RADIOTHERAPY AND PALLIATIVE TREATMENT 287 If disease persists or recurs, salvage cystectomy may still be successful in appropriately selected patients, 5y survival rates 30 \200\22350% (see b p. 284). Otherwise, cytotoxic ch emotherapy (see b p. 289) and palliative meas- ures may be considered. Palliative treatment RT (30 Gray) is effective for metastatic bone pain or to palliate symp to- matic (bleeding) local tumor (40 \200\22350 Gray). Intractable haematuria may be controlled by intravesical formalin or aAlum, hyperbaric oxyg en, bilateral internal iliac artery embolization or ligation, or palliative cystectomy/dive rsion. Ureteric obstruction may be relieved by percutaneous nephrostomy and antegrade stenting (see b pp. 363 and 546). Involvement of the palliative care team can be very helpful to the patient and family. CHAPTER 7 Urological neoplasia 288 Bladder cancer: management of locally advanced and metastatic disease Management of patient s with invasive bladder cancer requires a multidisci- plinary team approach, involving case -by-case discussion between the uro- logical surgeon, radiotherapist and medical oncologist , with support from the pathologist, radiologist, and cancer specialist nurse. Locally advanced bladder cancer (pT3b/4) Many patients treated with primary cystectomy or R T with curative in- tent succumb to metastatic disease due to incomplete tumor excision or micrometastases. Up to 50% of patients develop metastases, mostly at distant sites. At this stage, the 5y survival is only 25%. There is interest in augmenting primary treatment in a n effort to improve outcomes. Neoadjuvant and adjuvant RT Randomized studies have suggested improvements in local control (patho- logical downstaging) using RT (45 \200\22350 Gray in 25 fractions) 4 \200\2236 wee ks prior to cystectomy, but no survival bene \201 t has been demonstrated. The rationale f or post-cystectomy RT is that patients with proven residual or nodal disease may bene \201 t from locoregional treatment. However, it leads to unacceptably high morbidity and has no demonstrable advantages. Post-treatment bowel obstruction occurs 4.5 times more commonly i n RT patients. Adjuvant cystectomy Two studies have demonstrated an improvement in local control and a sur vival advantage when treating locally advanced disease with cystectomy after RT compared to RT alone. However, this treatment strategy does not happen in current UK practice, probabl y due to the increased morbid- ity of surgery in this setting. Neoadjuvant chemotherapy with cystectomy Preoperative chemotherapy is increasingly given to operable patients with non-metastatic T2 \200\223T4a disease. It may downstage the disease and treat micrometastases before the patient is debilitated by surgery. A meta- analysis o f 10 trials1 has suggested a 5 \200\2237% 5y survival advantage with the use of cisplatin-b ased combination chemotherapy prior to cystectomy compared with cystectomy alone. The absol ute gain was the same regard- less of stage; from 55 to 60% for T2, 40 \200\22345% for T3, and 25 \200\22330% for T4 patients. The relative gain was, therefore, greater for higher st age patients. One randomized trial demonstrated a median survival of advantage of 31 months in the group treated with neoadjuvant combination chemotherapy compared to the group recei ving cystectomy alone.2 Eligible patients must have a good performance status (<2 \200\224a mbulatory and able to carry out light work) and renal function (GFR >60mL/min). This treatm ent should be discussed with suitable patients suspected of having locally advanced or micr ometastatic disease prior to cystectomy. Adjuvant chemotherapy The rationale for post-cystectomy chemotherapy is that patients with proven residual or nodal disease may bene \201 t from systemic treatment. Trials have been hampered by protocol problems, small numbers, MANAGEMENT OF LOCALLY ADVANCED & METASTATIC DISEASE 289 surgical complications interfering with treatment, and dif \201 culty in assess- ing respo nse in the absence of measurable disease. However, two of four studies have shown a surviva l bene \201 t of almost 2y in the treated groups, using cisplatin-based regimes. Neoadjuvant or adjuvant chemotherapy with RT While controversial, neoadjuvant cisplatin-bas ed combination chemo- therapy with bladder preservation has been demonstrated to produce 5y survival rates of 42 \200\22372% when RT was used as de \201 nitive treatment. This may b e offered to patients suspected of having locally advanced disease after clinical examinati on and staging imaging. Metastatic bladder cancer Five percent of patients have metastatic disease at the time of d iagnosis. Systemic chemotherapy TCC is a chemosensitive cancer; it is recommended for patients with u n- resectable, diffusely metastatic measurable disease. Combination is more effective than single-agent treatment. A complete response is seen in 15% of patients given methotrexate, vinblastine, adriamycin, and cisplatin (MVAC), though 20% of patients develop neutropenia a nd 3% die of sep- sis. Median survival is 14 months. Most UK centers are using gemcitobine, an antimetabolite agent, alone or in combination with cisplatin. Complete responses are re ported in 25 \200\22340% of patients and it is better tolerated than MVAC, with 1% toxic de ath rate. Carboplatin may be used if cisplatin is contraindicated (i.e. performance status (cid:116)2 of GFR <60mL/min). Taxanes (paclitaxel and docetaxel) are microtubule disassembl y inhibitors; respons- es range from 25 to 80%, using these agents alone or in combination. Prognostic factors predicting response to chemotherapy include alka- line phosphatase, age >60y, performance status, and visceral metastases. Depending on the number of factors, medi an survival varies from 9 to 30 months.3 In future, molecular markers such as tumor p53 sta tus may be shown to predict chemosensitivity. Unfortunately, no biomarker is cur- rently av ailable to predict outcome, drive treatment decisions, or monitor response to treatment. Radiotherapy Roles for RT include palliation of metastatic pain, haematuria, and spinal cor d compression. Surgery There is no surgical role in treatment of extravesical metastatic disease. Palliati ve cystectomy or urinary diversion is justi \201 ed for severe local symptoms. 1 Advanced bladder cancer meta-analysis collaboration (2003) Neoadjuvant chemotherapy in in vasive bladder cancer: a systematic review and meta-analysis. Lancet 361:1927 \200\22334. 2 Grossman HB, Natale RB, Tangen CM, et al. (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859 \200\22366. 3 Bajorin DF, Dodd PM, Mazumbar M, et al. (1999) Long-term survival in metastatic transitio nal cell carcinoma and prognostic factors predicting outcome of therapy. J Clin Oncol 17:31 73 \200\22381. CHAPTER 7 Urological neoplasia 290 Bladder cancer: urinary diversion after cystectomy The choice of urinary diversion requires consideration of both clinical and quality of life (QoL) issues. Patients planned for cyst ectomy should be in- formed of the possible options. Contraindications to the continent re- constructive procedures include debilitating neurological and psychiatric illness, short l ife expectancy, and impaired renal or liver function. These patients must be motivated and able to perform ISC. Contraindications to orthotopic neobladder include tumor in the prosta tic urethra, wide- spread CIS, and urethral stricture disease. The majority of patients report good overall QoL following urinary diversion. The reconstru ctive procedures were expected to be better for social functioning compared to the ileal co nduit; most QoL studies have not shown signi \201 cant differences, although patients with continent diver- sions generally score more favorably in terms of body image, social activ - ity, and physical function. Ureterosigmoidostomy Dating back to 1821, the oldest form of urinary diversion, whereby the ureters drain into the sigmoid colon, either in its native form or following detubularizat ion and reconstruction into a pouch (Mainz II). This diversion requires no appliance (stoma bag, catheter) so remains popular in devel- oping countries. In recreating a \200\230cloa ca \200\231, the patient may be prone to upper UTI with the risk of long-term renal deterio ration, metabolic hyperchlo- raemic acidosis, and loose frequent stools. The low-pressure a nd capa- cious Mainz II pouch reduces, but does not abolish, these complications. Ileal conduit This was developed during the 1940 \200\231s by Eugene Bricker of St. Louis; it remains the most popular form of urinary diversion in the UK. Fifteen cm of subterminal ileum is isolated on its mesentery and the ureters are anastomosed to the proximal end. The distal end is brought out in the right iliac fossa as a stoma. The native ileum is anastom osed to gain enteral continuity. Complications of ileal conduit are: Prolonged ileus. Urinary leak. Enteral leak. Pyelonephr iris. Uretero-ileal stricture. Stoma problems (20% \200\224skin irritation, stenosis, and p arastomal hernia). Upper tract dilatation (30%). - - - - Patients require stomatherapy support and some \201 nd dif \201 culty in adjust- ing the ir lifestyle to cope with a stoma bag. Metabolic complications are uncommon. In post-RT salvage patients, a jejunal or colonic conduit is used because of concerns about the healing of radiation-damaged ileum. The conduit BLADDER CANCER: URINARY DIVERSION AFTER CYSTECTOMY 291 may be brought out in the upper abdomen and patients require careful electrolyte monitoring due to sodium loss and hyperkalaemia. Continent diversion The advantage is the absence of an external collection device. There ar e two types of continent diversion. - A right hemicolon. The ureters drain into this low-pressure balloon- shaped reservoir, usua lly through an antire \202 ux submucosal tunnel. This is drained by the patient via a cont inent catheterizable stoma, such as the appendix or uterine tube (the Mitrofanoff principle ) brought out in the right iliac fossa. A similarly constructed pouch may be anastomosed to the patient \200\231s urethra to act as an orthotopic neobladder so that natural voiding c an be established and no stoma is necessary. Patients void by relaxing their external sphin cter and performing a Valsalva. This neobladder should require no catheter, unless the pouc h is too large and fails to empty adequately. In this case, the patient must be prepared to perform ISC. continent pouch is fashioned from 60cm of detubularized ileum or Popular ileal pouches include those of Studer (see Fig. 7.4), Camey II, and Kock. Ileocaeca l pouches include the Indiana and Mainz I. Which one is chosen often comes down to the surg eon \200\231s preference; they carry similar complication risks. Previously irradiated bowe l can safely be used to form pouches though complications are more likely. Complications relating to pouches and neobladders are divided into early (12%) and late (37%). They include: - Urinary leakage and peritonitis. - Pelvic abscess. - Stone formation. - Catheterizing dif \201 culties and stomal stenosis. - Urinary incontine nce and nocturnal enuresis (particularly with neobladders). Pouch ureteric re \202 ux and Ureteropouch anastomotic stricture. Late neobladder rupture. - UTI. Metabolic abnormalities include early \202 uid and electrolyte imbalances; later, urinary electrolyte absorption may cause hyperchloraemic acidosis and loss of small bowel may resu lt in vitamin B12 de \201 ciency. Metabolic acidosis is less likely in patients with norma l renal function; treatment is with sodium bicarbonate and potassium citrate. Annual B12 mo nitoring should be undertaken with supplementation if necessary. Adenocarcinoma may develop (5%) in intestinal conduit, neobladder, or sigmoid colon mucosa in the long term due to the carcinogenic bacterial metabolism of urinary nitrosamines. This tends to occur near to the in \202 ow of urine. It is, therefore, advisable to perform an nual visual surveillance of urinary diversions after 10y. If the urethra is in situ, annual urethroscopy and cytology is important. CHAPTER 7 Urological neoplasia 292 (a) (b) (c) (d)