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Keywords:

  • clinical practice guidelines;
  • bladder cancer;
  • non-muscle invasive;
  • muscle invasive

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

In Japan, until now, the treatment of bladder cancer has been based on guidelines from overseas. The problem with this practice is that the options recommended in overseas guidelines are not necessarily suitable for Japanese clinical practice. A relatively large number of clinical trials have been conducted in Japan in the field of bladder cancer, and the Japanese Urological Association (JUA) considered it appropriate to formulate their own guidelines. These Guidelines present an overview of bladder cancer at each clinical stage, followed by clinical questions that address problems frequently faced in everyday clinical practice. In this English translation of a shortened version of the original Guidelines, we have abridged each overview, summarized each clinical question and its answer, and only included the references we considered of particular importance.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

The Japanese Urological Association (JUA) has previously published ‘General Rules for Clinical and Pathological Studies on Bladder Cancer’, with several revisions, but this is the first edition of their Clinical Guidelines for the Management of Bladder Cancer.

Internationally, a number of guidelines related to bladder cancer have been published, including those by the National Comprehensive Cancer Network (NCCN), the National Cancer Institute (NCI), Physician Data Query (PDQ), the American Urological Association (AUA), and the European Association of Urology (EAU). The diagnosis, classification and treatment of bladder cancer in Japan have been conducted in accordance with the JUA ‘General Rule’, based on the overseas guidelines. However, it has been pointed out that the recommended options based on overseas guidelines and other references are not always suitable for Japanese clinical practice, with some medications and therapeutic equipment not licensed for use in Japan. As the reader will understand after referring to the reference list for these Guidelines, a relatively large number of clinical trials has been conducted in Japan in the field of bladder cancer, and hence the JUA considered it appropriate to formulate their own guidelines.

In general, when formulating clinical guidelines, it is normal to classify disease according to patient risk. The tumor-nodes-metastasis classification (TNM) and American Joint Committee on Cancer (AJCC) classifications are widely used worldwide, but a number of different, more detailed, classifications of risk have been proposed internationally, with no general consensus at present. For example, it would be rather pointless to propose one's own risk classification of non-muscle-invasive bladder cancer (NMIBC), based on Western guidelines, without sufficient clinical trial data for support. The challenge for us now is to produce a new risk classification based on a meta-analysis of the results of multiple clinical trials. The risk classifications contained in the clinical questions (CQ) and their answers in these Guidelines will therefore differ somewhat from the references on which they are based. However, we have followed the general worldwide consensus for NMIBC, recommending that the low-risk group receive one instillation of chemotherapy, the intermediate-risk group receive multiple instillations of chemotherapy or bacillus calmette-guérin (BCG), and the high-risk group receive either intravesical BCG immunotherapy or total cystectomy.

These Guidelines present an overview of bladder cancer at each clinical stage, followed by CQ that address problems frequently faced in everyday clinical practice. We tried to provide as broad an exposition of each CQ topic as possible, and refer to as many related areas as we could, but considering the nature of these Guidelines it is extremely difficult to cover every specific circumstance in a satisfactory manner. In the future, we plan to revise these Guidelines at appropriate intervals, incorporating the opinions of specialists working in the field, adding new medications as they come to light, and adding data from relevant clinical trials.

In this abridged English version, due to space constraints, we have abridged each overview, and summarized each CQ and its answer. We have included only those references we considered of particular importance. The reference numbers have been changed to be consecutive for the English version, and will differ from the original Guidelines.

Evidence for these Guidelines

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

These Guidelines were formulated in accordance with the ‘Japan Society of Clinical Oncology – Guidelines for Developing Cancer Treatment Guidelines Ver. 4’. The Formulation Committee first set out the 49 CQ. With the assistance of the Japan Medical Library Association, they conducted a literature search of PubMed and Japana Centra Revuo Medicina for each CQ, examining papers published over the preceding 10-year period. Relevant papers were selected, with the addition of new papers with a high evidence level published during the guideline production process. Committee members added abstracts and other important evidence not yet included in PubMed, and the Committee discussed the appropriateness of each piece of evidence before inclusion in the bank of evidence.

The level of evidence of each paper was graded as follows: Level I, systematic review or meta-analysis; Level II, at least one randomized controlled trial; Level III, non-randomized controlled trial; Level IVa, analytical epidemiological study, cohort study; Level IVb, analytical epidemiological study, case-control study or cross-sectional study; Level V, descriptive study (case report or case series); and Level VI, expert opinion, individual or committee, not based on patient data. The grade of recommendation for the answer to each CQ was given as follows: (A) strongly recommend this action; (B) recommend this action; (C) no firm evidence for recommendation; and (D) recommend against this action. Determination of the ‘grade of recommendation’ was generally made in accordance with the ‘Guidelines for Developing Cancer Treatment Guidelines’, but in cases where evidence was scant or decisions had to be made with a low level of evidence, we followed the procedures for ‘consensual recommendation’, reflecting discussion and agreement between Committee members.

I. Epidemiology and diagnosis (Fig. 1)

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix
image

Figure 1. Diagnostic algorithm of bladder cancer. CT, computed tomography; MRI, magnetic resonance imaging.

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CQ 1: Is primary prevention of bladder cancer possible?

Answer

Epidemiological studies have shown that the most effective way of preventing bladder cancer is to refrain from smoking. Lactobacillus casei strain Shirota has been reported to prevent recurrence of bladder cancer. Taking vitamins A, C and E might also have preventative effects,but there have been conflicting reports, and therefore further studies confirming these effects are needed. (Grade of recommendation B.)

Explanation

Primary prevention methods have been identified for bladder cancer. Already confirmed at the clinical level are ingestion of lactobacillus1,2 and vitamins A, C and E.3,4 For each of these, initial studies have yielded positive results indicating reduced incidences and disease-specific mortality rates, whereas follow-up studies have often yielded contradictory results,4,5 so no conclusions have been reached. Other substances that have been identified as possibly protective against bladder cancer include isoflavons, lycopene and selenium. Regarding medications, several case-control studies have suggested that the use of nonsteroidal anti-inflammatory drugs (NSAIDs), excluding phenacetin, might be effective in preventing bladder cancer.6

CQ 2: Is there a link between smoking and bladder cancer?

Answer

Although not as strong as for cancers of the respiratory tract, there is a strong correlation between smoking and bladder cancer. Smoking is therefore considered to be one of the causes of bladder cancer. (Grade of recommendation A.)

Explanation

The risk of developing bladder cancer is two- to four-times greater in smokers than non-smokers. The disease-specific mortality rate is also approximately twice as high in smokers than non-smokers. A meta-analysis by the World Health Organization (WHO) International Agency for Research on Cancer (IARC) found a positive correlation between the duration of smoking and the number of cigarettes smoked per day and an increased risk of developing bladder cancer.7

A 2006 multicenter prospective trial found that the incidence of bladder cancer in present smokers and those with a history of smoking was 3.96 and 2.25 times, respectively, greater than in those who never smoked. A strong correlation was also reported between smoking and developing bladder cancer, with positive correlations with the time of starting smoking, duration of smoking and the number of cigarettes per day.8 Data analysis from the Japanese Urological Association (JUA) bladder cancer register revealed that the onset of bladder cancer is 5–6 years earlier in male than female smokers.9

CQ 3: Are there any urine markers useful for screening bladder cancer?

Answer

Due to various reasons, including the low overall prevalence of bladder cancer, the prevailing opinion is that bladder cancer screening is not a useful addition to routine health checks. If we confine the discussion to the high-risk group, such as people with a history of occupational exposure to carcinogenic substances and elderly people with a history of smoking, then the most effective screening method would be urinalysis and urine cytology on an annual basis. (Grade of recommendation C.)

Explanation

Reagent strip urinalysis for microscopic hematuria is the only screening test for bladder cancer as part of a routine health check whose efficacy has been adequately investigated. In a large scale study with the general population,10 hematuria was detected in approximately 20% of those screened, with bladder cancer detected in 6–8% of subjects positive for hematuria.

The reported sensitivity for urine cytology is 40–60%, and the specificity 90–100%, with a low ability to detect well-differentiated NMIBC the reason for the low sensitivity.11 This suggests that urine cytology might be useful in screening high-risk groups with a high proportion of tumors that have a high degree of atypia, such as people with a history of occupational exposure to carcinogenic substances.

In recent years, several new molecular markers associated with bladder cancer have been developed, and in Japan several have been approved for medical insurance coverage, including nuclear matrix protein 22 (NMP22)12 and the bladder tumor antigen test (BTA test).13 These show a somewhat higher sensitivity than urine cytology, even for tumors with a low degree of atypia, but have the problem of a high false-positive rate in cases of macroscopic hematuria, urolithiasis or urinary tract infection. Accordingly, they are not yet used widely as diagnostic markers.14

CQ 4: What imaging modalities are useful in diagnosing and staging bladder cancer?

Answer

When muscle-invasive bladder cancer is suspected clinically, T staging is performed using pelvic computed tomography (CT) or magnetic resonance imaging (MRI) scanning. As bladder cancer tends to metastasize to lymph nodes, the liver and lung, CT scanning of the chest and abdomen is useful for N and M staging. (Grade of recommendation B.)

Explanation

Transabdominal ultrasonography is a simple and effective imaging modality, but in some bladder cancers its accuracy might suffer depending on the tumor size and site.

Intravenous urography (IVU) is useful in eliminating further urothelial tumors arising in the upper urinary tract, but is not necessary in all patients because the incidence of upper urinary tract tumors at the time of diagnosis of a bladder cancer is of the order of 0.3–2.3%.15

The diagnostic accuracy of staging of the primary tumor using CT and MRI is not particularly high. However, both modalities are useful in detecting bladder cancer extramural invasion and lymph node metastases, and should be performed whenever muscle invasive bladder cancer is suspected, before transurethral resection of bladder tumor (TURBT) is considered.

II. Treatment of NMIBC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ 1: How far should you resect when performing TURBT?

Answer

We recommend that during a TURBT all visible tumors should be resected wherever possible. NMIBC cannot be diagnosed until muscularis propria is included in the resected tissue and confirmed to contain no tumor cells. The peritumor area also needs to be sampled. (Grade of recommendation A.)

Explanation

The aims of TURBT in cases of NMIBC are to obtain accurate staging and resect as much of the lesion as possible.16 Pedunculated tumors less than 1 cm in size, initially thought to be low grade Ta lesions, can be resected in one piece and this will suffice for a tissue diagnosis as long as normal tissue has been sampled at the tumor base.16 On the other hand, removal in one piece is inadequate for large tumors suspected of being high grade or invasive, or with a nodular, wide-based or ulcerated appearance. It is necessary to confirm that the cancer has not invaded the muscularis propria, and it is therefore important to resect the lesion so that the muscularis propria and adjacent tissue are also sampled.16–18

CQ 2: Are random biopsies including the prostatic urethra recommended at TURBT?

Answer

Random biopsies at TURBT are recommended when concomitant carcinoma in situ (CIS) is suspected. (Grade of recommendation A.) Biopsy of the prostatic urethra is also recommended when the tumor is situated in the trigone or bladder neck, or if multiple tumors are present. (Grade of recommendation B.)

Explanation

The value of random biopsies, a matter of debate for some time, depends on the risk classification of the main tumor.

The EAU Guidelines do not recommend random biopsies routinely for TaT1 tumors.16 In particular, in the case of low risk tumors, the random biopsy detection rate for malignant lesions is extremely low at 1.5%.19 This is evidenced by the fact that the choice of agent for postoperative intravesical instillations is not influenced by the results of random biopsies. The random biopsy detection rate for malignant lesions rises to 11.6% with medium- to high-risk tumors;19 however, the EAU Guidelines recommend random biopsies in cases with positive urine cytology and non-papillary tumors.16 The NCCN Guidelines also take the stance of recommending random biopsies in CIS cases.18

The indications for prostatic urethral biopsies include tumors situated in the trigone or bladder neck, CIS and multiple tumors.20 The recommended method for prostatic urethral biopsy is by transurethral resection.16,21 From the results of detailed examinations of total vesicourethrectomy specimens, one report recommended tissue samples be taken from the 5 and 7 o'clock positions of the verumontanum portion of the prostate where cancer invasion is more commonly seen.22

CQ 3: Is a second TURBT, or re-TURBT, recommended for NMIBC?

Answer

A second TURBT (re-TURBT) is recommended for cases with high-grade T1 pathohistological findings, or cases with no muscularis propria in the resected specimens. (Grade of recommendation A.)

Explanation

When the initial TURBT is followed by a second TURBT in cases of TaT1 tumors, residual cancer is detected in 22–72% of cases with Ta lesions and 20–78% with T1 lesions.23 In addition, the initial histological findings are reportedly upstaged to T2 by the reviewing pathologist in 2–28% of cases.24,25 This understaging at the initial TURBT cannot be ignored when considering the patients' prognosis. The timing of the second TURBT is usually 1–8 weeks after the initial procedure, with an interval of 4–6 weeks particularly common.24,25 In addition to any visible tumor, the second procedure should concentrate on the initial resection site, removing scar tissue at the base of the initial resection site, as well as any edematous tissue in the vicinity. Tissue specimens must contain muscularis propria.23,25,26

CQ 4: Is there a recommended follow-up protocol following initial treatment?

Answer

Following initial treatment, it is usual to perform cystoscopy 3 months later, and subsequently alter the interval between examinations according to the risk profile, although a consensus has not been reached over an appropriate protocol. (Grade of recommendation B.)

Explanation

Evidence to support the development of an optimum protocol for follow up of NMIBC is lacking. Regarding the frequency of cystoscopies and the interval between them, the EAU Guidelines state that a follow-up protocol should be devised reflecting the likelihood of recurrence and progression for each individual patient.27

The EAU and NCCN Guidelines both recommend cystoscopy 3 months after the initial TURBT, and consider that the results of the first postoperative examination provide important information for prediction of possible disease recurrence and progression.28

For patients with tumors at low risk of recurrence and progression, the EAU Guidelines recommend cystoscopy 3 months after the initial procedure, and if the findings are negative, yearly thereafter for a further 5 years. For patients with tumors at high risk of progression, if the findings of the cystoscopy 3 months after the initial procedure are negative, they recommend cystoscopies every 3 months for 2 years, every 4 months in the third year, and every 6 months for the fourth year, then yearly thereafter, along with a yearly exploration of the upper urinary tract. They recommend that patients with tumors at intermediate risk of progression should have an in-between follow-up scheme adapted to each individual.16

For patients with low-grade Ta tumors, the NCCN Guidelines recommend cystoscopy 3 months after the initial procedure and at appropriate intervals thereafter. For patients with low-grade T1and high-grade TaT1 tumors, they recommend cystoscopies and urine cytology every 3 months for 2 years, every 6 months for the next 2 years, then yearly cystoscopies thereafter. For patients with high-grade tumors, they recommend exploration of the upper urinary tract every 1–2 years, and include options such as measurement of urothelial tumor markers.18

In formulating a risk classification for Japanese guidelines for NMIBC, it is a matter of some debate as to whether we should follow our own counsel, making clear any differences with Western thinking, or take a global comparative stance. Using a system that matches overseas classifications to a certain extent, we defined the low-risk group as: initial disease, single lesion, size <3 cm, Ta, low grade, with no CIS. Conversely, the high-risk group is T1, high grade or CIS (including concomitant CIS), and multiple lesions or recurrent disease. The remainder should fall into the intermediate-risk group, including Ta-1, low grade, no concomitant CIS, and multiples lesions or size ≥3 cm. This classification leaves Ta, high-grade disease not included in any risk group, but this is extremely rare clinically and if it is encountered an overall assessment should be made based on other clinical factors. Based on the above draft risk classification, we will continue with the following CQ.

CQ 5: What additional investigations are recommended if positive urine cytology persists despite negative bladder findings following TURBT?

Answer

If there are no abnormal bladder findings but positive urine cytology persists, random biopsies, including transurethral biopsies of the prostatic urethra, bilateral upper urinary tract cytology and, if necessary, ureteroscopic exploration of the upper urinary tract are recommended. (Grade of recommendation B.)

Explanation

During post-TURBT follow up, when positive urine cytology persists despite no abnormalities being detected on cystoscopy or imaging, it is important to investigate further, mindful of the possibility of CIS.18 Random intravesical biopsies, as well as transurethral biopsies of the prostatic urethra, bilateral upper urinary tract cytology and ureteroscopy are recommended. If all of these results are negative, repeating cystoscopy, bilateral upper urinary tract cytology and ureteroscopy at 3-month intervals is recommended. If bladder findings become positive, intravesical BCG immunotherapy, change of chemotherapy agent or total cystectomy is recommended. If exploration of the upper urinary tract yields positive findings, after staging of the renal pelvic and ureteric cancer, surgery or systemic chemotherapy appropriate to the stage is recommended.18

CQ 6: Is one immediate postoperative intravesical instillation of chemotherapy recommended for low-risk NMIBC?

Answer

One immediate postoperative intravesical instillation of chemotherapy is recommended for low-risk NMIBC. (Grade of recommendation A.)

Explanation

Even for cancers at low risk for recurrence and progression, the reported recurrence rate is of the order of 45% for TURBT alone.29 The efficacy of one immediate postoperative intravesical instillation of chemotherapy has been shown in randomized controlled trials (RCT), and meta-analyses have confirmed the efficacy of a single instillation of mitomycin C (MMC),29 pirarubicin (THP-ADM),30 or epirubicin31 in preventing recurrence, with no differences in efficacy between these agents.32 One immediate postoperative intravesical instillation of chemotherapy is also highly cost effective.16,30 A single instillation has been shown to be ineffective for multiple tumors, and is considered the standard treatment for low risk single tumors only.32

The timing of the instillation is often reported within 6 h of surgery,29,30 and the EAU and NCCN Guidelines recommend a single instillation within 24 h of TURBT. The relative risk of recurrence increases twofold if the instillation is not performed on the same day as the TURBT.16,18

Following intravesical instillation of chemotherapy, many report clamping the catheter for 1 h.29,30 Immediate instillation should be avoided in case of overt or suspected bladder perforation during the TURBT.16

CQ 7: Is maintenance chemotherapy recommended for intermediate-risk NMIBC?

Answer

As adjuvant therapy for intermediate-risk NMIBC following TURBT, one immediate postoperative intravesical instillation of chemotherapy followed by maintenance chemotherapy is recommended (Grade of recommendation A), although a consensus has not been reached regarding the schedule for maintenance chemotherapy.

Explanation

One immediate postoperative intravesical instillation of chemotherapy is also recommended for intermediate-risk NMIBC. Further intravesical instillations of chemotherapy are also necessary due to the increased risk of recurrence and progression.

A large-scale RCT of intravesical instillations of anthracycline chemotherapy was conducted in Japan, confirming significant reduction in recurrence in comparison with the TURBT only group.33,34 Investigations of different chemotherapy agents, concentration of the intravesical solution, number of instillations and duration of treatment have shown that the concentration is more important than the duration of treatment.35

The duration of the prevention of recurrence by maintenance chemotherapy is said to be no longer than 500 days.36 Maintenance chemotherapy prevents recurrence but does not reduce the risk of disease progression.37 A number of problems are yet to be resolved.

CQ 8: Is BCG immunotherapy the recommended instillation regimen for high-risk NMIBC?

Answer

BCG immunotherapy is the recommended adjuvant therapy for high-risk NMIBC following TURBT (Grade of recommendation A), although a consensus has not been reached regarding the instillation regimen.

Post-TURBT BCG immunotherapy has been confirmed to inhibit both recurrence and progression of high-risk NMIBC.38 The BCG treatment regimen in Japan is generally 6–8 weekly instillations of Japan strain 80 mg or Connaught strain 81 mg.39–41

Adverse reactions to BCG immunotherapy are a considerable problem, prompting studies of low-dose BCG instillation regimens. An overseas study using the BCG Connaught strain in patients with high-risk NMIBC compared the standard dosage of 81 mg/instillation and a one-third dosage of 27 mg/instillation finding the same efficacy against progression in both groups, but significantly less toxicity in the low dosage group.42 Further studies examining low-dose immunotherapy for patients with high-risk NMIBC, with the aim of minimizing BCG toxicity, are in progress, but a conclusion is yet to be reached.

CQ 9: Is maintenance BCG immunotherapy recommended for high-risk NMIBC?

Answer

Maintenance BCG immunotherapy is recommended for high-risk NMIBC following TURBT. (Grade of recommendation B.)

Explanation

BCG immunotherapy is recommended for high-risk NMIBC to prevent postoperative recurrence and progression.38,43

A Southwest Oncology Group (SWOG) RCT administered six instillations of BCG immunotherapy to all subjects with high-risk NMIBC, then randomized subjects to 3 weeks of maintenance BCG immunotherapy every 3 months for 3 years, or no further treatment. They found significantly improved recurrence-free and progression-free survival rates in the maintenance therapy group.44 However, the completion rate in the maintenance therapy group was only 16%, indicating a major problem with toxicity at the same time as confirming efficacy.

A meta-analysis of RCT of maintenance BCG immunotherapy found that despite the wide variety of instillation regimens, progression was inhibited by 27%.38 Maintenance BCG immunotherapy is therefore recommended for high-risk NMIBC to prevent disease progression. At present, a consensus has not been reached regarding the concentration of the intravesical solution or instillation schedule.

CQ 10: What treatments are recommended for patients with recurrent low- to intermediate-risk NMIBC?

Answer

BCG immunotherapy or, if necessary, total cystectomy, is recommended for patients with recurrent low- to intermediate-risk NMIBC. (Grade of recommendation B.)

Explanation

The choice of treatment for patients with recurrent low- to intermediate-risk NMIBC should be based on the likelihood of further recurrence and progression. In particular, maintenance BCG immunotherapy is an option in cases of recurrent low-risk NMIBC following post-TURBT intravesical instillation of BCG or MMC, even if there are no malignant findings at re-TURBT. A change in the chemotherapy agent or total cystectomy is recommended for recurrent Tis or Ta tumors, and total cystectomy for recurrent high-grade T1 disease.18 If urine cytology is positive in a patient with low-risk NMIBC, despite no detectable disease on cystoscopy or imaging, random intravesical biopsies as well as transurethral biopsies of the prostatic urethra should be performed. If there are positive bladder findings, intravesical BCG immunotherapy is recommended and maintenance BCG immunotherapy is an option, if necessary. Furthermore, if prostatic urethral biopsies are positive due to invasion of the prostatic parenchyma or gland, total cystectomy with prostatic urethrectomy might be recommended.18

CQ 11: Is second line BCG immunotherapy recommended for recurrent high-risk NMIBC?

Answer

Second-line BCG immunotherapy can be performed for recurrent high-risk NMIBC with caution regarding toxicity, and total cystectomy should be performed, if necessary. (Grade of recommendation B.)

Explanation

The NCCN Guidelines recommend up to two courses of intravesical BCG immunotherapy or MMC chemotherapy and TURBT. If no tumor is present at TURBT, maintenance BCG immunotherapy is an option. In cases of Tis or Ta tumors, they recommend a change in the chemotherapy agent or total cystectomy, and total cystectomy for high-grade T1 tumors.18

The EAU Guidelines strongly recommend immediate total cystectomy for recurrent high-risk NMIBC. When a tumor is detected 3 months after the first course of intravesical BCG immunotherapy, complete response (CR) is achieved in over 50% of cases with the second course of BCG, irrespective of whether it is a papillary tumor or CIS. However, there is a high possibility that during BCG immunotherapy disease will recur, the depth of invasion or degree of atypia will increase, or in cases with CIS it will progress to muscle-invasive bladder cancer.18 There have been no RCT comparing therapeutic results between total cystectomy and second-line BCG immunotherapy in patients with high-risk NMIBC following the first course of BCG. Early total cystectomy has been reported to improve survival in high-risk patients with BCG-resistant tumors,45 and some authors propose total cystectomy as the standard treatment.46

From the above, second-line BCG immunotherapy is sometimes recommended for recurrent high-risk NMIBC, but it should be administered with every caution.

CQ 12: Is there a recommended timing for total cystectomy for high-risk NMIBC?

Answer

In patients with high-risk NMIBC at high risk of disease progression, total cystectomy is recommended when residual tumor is suspected following second-line BCG immunotherapy. (Grade of recommendation B.)

Explanation

The most important point when considering total cystectomy in patients with high-risk NMIBC is to determine how high the risk of disease progression is. Based on a table setting out the risks of recurrence and progression, the EAU Guidelines recommend total cystectomy for multiple or recurrent high-grade tumors, high-grade T1 tumors, and high-grade tumors with concomitant CIS.16 The NCCN Guidelines are on similar lines, but differ somewhat in that MMC is included in an option for intravesical instillation along with BCG, and that the decision is made after two courses of intravesical therapy.18

The timing of elective total cystectomy will tend to be either 3 months after TURBT or after one or two courses of intravesical therapy. Total cystectomy is recommended when the cystoscopic findings are of one of the abovementioned high-risk tumor types. In particular, with tumors with concomitant CIS or prostatic invasion, some reports state that cystectomy after a second course of intravesical BCG immunotherapy is too late.47

III. Treatment of CIS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ 1: Is there a recommended BCG regimen for CIS?

Answer

The recommended regimen for intravesical BCG immunotherapy for CIS is once weekly for 6–8 weeks. (Grade of recommendation A.)

Explanation

According to the NCCN and EAU Guidelines, and the NCI PDQ, the recommended regimen for intravesical BCG immunotherapy is once weekly for 6 weeks.18,48 The BCG strains used in Japan are the Japan and Connaught strains, with recommended dosages of 80 mg and 81 mg, respectively.39,40 The recommended regimen for intravesical BCG immunotherapy for CIS is therefore once weekly for 6–8 weeks.

CQ 2: Is maintenance BCG immunotherapy recommended for CIS?

Answer

Maintenance BCG immunotherapy is recommended for CIS. (Grade of recommendation B.)

Explanation

According to the most recent AUA, NCCN, EAU and NCI PDQ, maintenance BCG immunotherapy is recommended for CIS after completion of the initial BCG therapy.49–51 The RCT conducted by Lamm et al. found a significantly lower recurrence rate in the maintenance BCG immunotherapy group than in the untreated group.44 A meta-analysis by Sylvester et al. comparing the efficacy of intravesical instillations of MMC and intravesical BCG immunotherapy (once weekly for 6 weeks) in patients with CIS found no significant difference between treatments. The addition of maintenance BCG immunotherapy to the initial 6 week course provided a significantly better therapeutic effect than intravesical MMC, indicating the usefulness of maintenance BCG immunotherapy.52 A number of institutions follow standard BCG immunotherapy (once weekly for 6 weeks) with further intravesical instillations of BCG (once weekly for 3 weeks) at 3, 6, 12, 18, 24, 30 and 36 months. At present, maintenance BCG immunotherapy is therefore recommended for CIS.

CQ 3: Is second-line BCG immunotherapy recommended for CIS for initial BCG failure or recurrent disease?

Answer

Second-line BCG immunotherapy is recommended for CIS, for either initial BCG failure or recurrent disease. (Grade of recommendation B.)

Explanation

The NCCN and EAU Guidelines recommend second-line BCG immunotherapy for CIS, for either initial BCG failure or recurrent disease, although there is a lack of high-level evidence from RCT.46,50 The AUA Guidelines suggest second-line BCG immunotherapy as a treatment option in these cases.49 A number of studies have shown the usefulness of second-line BCG immunotherapy for CIS, either for initial BCG failure or recurrent disease.53 However, therapeutic efficacy cannot be expected for second-line BCG immunotherapy in BCG-refractory cases.54

CQ 4: Is there a recommended timing for total cystectomy for CIS?

Answer

Total cystectomy is recommended for CIS lesions when second-line BCG immunotherapy is ineffective. (Grade of recommendation B.)

Explanation

No high-evidence level randomized RCT have examined the optimum timing for total cystectomy for CIS lesions. According to the most recent NCCN and NCI PDQ, total cystectomy is recommended for CIS lesions, for either second-line BCG failure or recurrent disease.50,51 The AUA and EAU Guidelines suggest total cystectomy as a treatment option in these cases.49 The reason for this is that in many cases, while third-line BCG immunotherapy is being administered, the lesion being treated has progressed to muscle-invasive or metastatic bladder cancer.55 At present, the recommended timing for total cystectomy is when a lesion has been assessed as BCG-refractory following initial therapy,54 or when second-line BCG immunotherapy is ineffective.

IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ1: What are appropriate methods of clinical T staging?

Answer

MRI and CT scanning are used for clinical T staging, although the diagnostic accuracy for muscle invasion is low for both modalities. TURBT must be performed to obtain an accurate assessment of muscle invasion. Furthermore, re-TURBT is recommended for high-grade tumors such as T1G3 lesions. The diagnostic accuracy for extramuscular invasion is higher than that for muscle-invasive bladder cancer, but in either case there is a strong tendency for understaging. (Grade of recommendation B.)

Explanation

MRI and CT scanning are used for clinical T staging. Overall, the diagnostic accuracy for T staging is higher with MRI.56 CT scanning cannot reliably distinguish between NMIBC and muscle-invasive bladder cancer. For this purpose, the diagnostic accuracy of MRI is basically similar, but it might be able to exclude invasion of the muscularis propria by pedunculated tumors. TURBT is the best method for accurate diagnosis of muscle invasion, for which it is essential to resect sufficient muscularis propria.26 The diagnostic accuracy of extramuscular invasion is similar with MRI and CT scanning, although MRI is superior for detection of invasion of adjacent organs.

CQ 2: What are the best imaging modalities for the detection of lymph node and distant metastases?

Answer

MRI is superior to CT for the detection of lymph node metastases, but both modalities are affected by the degree of lymph node enlargement. CT scanning is used for the detection of lung metastases. Bone scintigraphy is used to detect bone metastasis, although it is uncertain whether it is necessary in all patients with muscle-invasive bladder cancer. (Grade of recommendation B.)

Explanation

MRI and CT scanning detect lymph node metastases through enlargement and abnormal morphology of the lymph nodes, so their diagnostic accuracy is influenced by the degree of lymph node enlargement (usually ≥1 cm). No difference is seen between the two modalities in 2-D assessments, but the superiority of MRI becomes evident when 3-D techniques are used, reaching a diagnostic accuracy of 90%.57 At present, positron emission tomography (PET) scanning does not have a superior ability to detect lymph node or distant metastases over MRI.

Plain chest radiography and CT scanning are used to examine the lungs. This should be performed before commencing treatment for muscle-invasive bladder cancer.

No firm consensus has been reached as to whether investigations looking for bone metastasis are necessary in all patients with muscle-invasive bladder cancer.

Bone scintigraphy is performed in patients with elevated alkaline phosphatase levels or bone pain, but is not a routine investigation. Areas positive for bone scintigraphy should also be evaluated using MRI.

CQ 3: What follow-up examinations should be conducted following total cystectomy for stage II and stage III bladder cancer? At what frequency should radiological examinations be performed?

Answer

Surveillance following treatment for muscle-invasive bladder cancer should look for the following: (i) cancer recurrence (local, distant organs and urethral remnant); (ii) upper urinary tract cancer; and (iii) upper urinary tract changes or metabolic abnormalities associated with urinary tract diversions. There are no established intervals for each examination, but they should be performed at least every 3–6 months for the first 2 years after surgery, and annually thereafter. These intervals should be set after due consideration of the degree of malignancy and level of progression of the cancer. (Grade of recommendation B.)

Explanation

Intrapelvic recurrences were seen in approximately 20% of patients who underwent radical cystectomy.58 CT and MRI are useful in the detection of intrapelvic recurrences, although MRI is superior in delineating soft tissues.

Recurrences in the urethral remnant were seen in 10–15% of patients who underwent radical cystectomy.59 In urinary tract diversions other than a continent neobladder procedure, where the urethra is not amputated, urethral washings cytology is useful for the early detection of recurrence. The usefulness of urine cytology in patients with a continent neobladder, such as an ileal neobladder, is uncertain. Endoscopic confirmation is required if recurrence in the urethral remnant is suspected from washings cytology.

Evaluation of distant metastases concentrates on the lungs. Plain chest radiography and CT scanning are both used, the latter more commonly in Japan.

The cumulative incidence of upper urinary tract cancer in patients with muscle-invasive bladder cancer is 4% at 3 years, and 7% at 5 years, maintaining a similar incidence from then on.60 Intravenous urography (IVU) was previously used for surveillance of the upper urinary tract, but has a low diagnostic accuracy. A different method is needed, but a superior modality that can replace IVU does not exist at present. Multislice CT urography holds promise for the future. Urine cytology is useful, but its sensitivity is low, so it is used in conjunction with IVU.

CQ 4: What are the standard treatments for stage II and stage III bladder cancer?

Answer

The standard treatment for muscle-invasive bladder cancer is radical cystectomy plus pelvic lymphadenectomy. The merits of increasing the extent of the lymphadenectomy have not been fully established. (Grade of recommendation A.)

In terms of perioperative chemotherapy, the efficacy of cisplatin-based combination chemotherapy regimens, such as neoadjuvant MVAC (methotrexate, vinblastine, doxorubicin and cisplatin), has been reported. (Grade of recommendation A.) However, it cannot be said that this is the standard treatment in routine clinical practice.

Explanation

The most important considerations in applying the standard treatment for muscle-invasive bladder cancer are accurate staging and appropriate patient selection. Age is not always an impediment to implementing this standard treatment, but careful evaluation including performance status and the American Society of Anesthesiologists (ASA) physical status classification is essential.

Some reports include the common iliac and median sacral lymph nodes in pelvic lymphadenectomy. There has been no standardization of the extent of the lymphadenectomy, or the number of lymph nodes to be excised. In general, 15 nodes are resected in a regional adenectomy, 20–30 in an adenectomy up to the aortic bifurcation, and 30–40 in an adenectomy up to the level of the inferior mesenteric artery. It is possible that the number of lymph nodes resected influences the survival rate,61 although it is unclear at present whether this applies to all disease stages.

Studies of the effects of perioperative chemotherapy have shown the efficacy of cisplatin-based combination chemotherapy regimens, such as neopreoperative MVAC. No studies have shown clear efficacy for any adjuvant chemotherapy regimens.

CQ 5: In terms of therapeutic effect, what is the comparison between radical surgery and palliative treatment (TURBT alone or partial cystectomy alone)?

Answer

Bladder preserving therapies, either TURBT alone or partial cystectomy alone, are not standard treatment for muscle-invasive bladder cancer. They are indicated for patients unsuitable for curative therapy such as radical cystectomy. If bladder preservation is the aim, a multidisciplinary approach combining one of these surgical methods with chemotherapy or radiotherapy (or both) is essential. (Grade of recommendation B.)

Explanation

Bladder preservation is possible in patients with muscle-invasive bladder cancer, although by no means are all patients suitable.62 It is usually performed in combination with chemotherapy and radiotherapy.62,63 Patients with muscle-invasive bladder cancer indicated for TURBT alone or partial cystectomy alone will be those with relatively early muscle-invasive bladder cancer only, and those unsuitable for radical cystectomy or multidisciplinary bladder preserving therapy.

CQ 6: What are the indications for bladder preserving therapy? CQ 7: What bladder preserving therapies are available, and what are their therapeutic results?

Answer

Bladder preserving therapy, a combination of TURBT, chemotherapy and radiotherapy, is possible in some patients with muscle-invasive bladder cancer. The indications are clinical stage T2 or T3 disease and a small number of tumors that are small in size, although strict indications have not been established. Within the abovementioned triple combination therapy, a number of different treatment regimens exist. (Grade of recommendation B.)

Explanation

Bladder preserving therapy first involves TURBT, resecting as much tumor as possible, followed by chemotherapy and radiotherapy. Remnant tumor and staging are then evaluated by re-TURBT.64 Chemotherapy regimens include monotherapy with cisplatin, a radiation-sensitizing agent, or multiple agents.62,63,65 The reported route of administration for chemotherapy is usually intravenous in most Western countries, whereas intra-arterial administration is more common in Japan. Radiation doses also vary considerably, although many are within 60–70 Gy.

According to Rödel et al. the ideal candidate for bladder preserving therapy has a single and relatively shallow muscle invasive bladder cancer that can be completely resected at the initial TURBT.62 Miyanaga et al. investigated selection of appropriate patients for bladder preserving therapy through scoring clinicopathological factors, finding that bladder preservation was possible in 60% of patients with T2N0M0 disease, and 33% of those with T3N0M0 disease.63

CQ 8: What are the therapeutic results achieved with radical cystectomy plus lymphadenectomy?

Answer

Radical cystectomy plus lymphadenectomy is the standard treatment for muscle-invasive bladder cancer with no clinical evidence of lymph node metastases. At present, in terms of control of the primary tumor, no other treatment can promise better therapeutic results. (Grade of recommendation A.)

For pN1 lymph node metastases, in some cases, a cure can be achieved with this standard treatment. However, for pT3-4 and pN+ disease the therapeutic results are generally less than satisfactory. (Grade of recommendation B.)

Explanation

Collating the results of a number of reports published since 2001, 5-year survival rates following radical cystectomy plus lymphadenectomy were 62–84% for patients with pT2pN0 disease (pT2a 77–84%, pT2b 66–69%), 31–59% for pT3pN0, 30–49% for pT4pN0, and 21-35% for pN+.64,66–68 In another analysis with 4110 patients, lymph node metastases were detected in 24% of patients, stratified for depth of invasion in 9% (this number, or the range, is obviously wrong) of patients with pT2a disease (9–18%), 30% with pT2b (22–41%), 46% with pT3 (41–50%), and 49% with pT4 (41–63%).69 Lymph node metastasis is in itself a prognostic factor for muscle-invasive bladder cancer, and some other factors that influence the therapeutic result are the number of metastatic lymph nodes, the lymph node density (proportion of metastatic lymph nodes) and the number of lymph nodes resected.70

The mortality rate for radical cystectomy plus lymphadenectomy was less than 4% in a recent study.71 The reported incidence of early complications (within 1 month postoperatively) is 30–40%, and for serious complications it is less than 10%.71 This procedure can therefore be performed safely, even in older patients.72 Even if the range of the lymphadenectomy is extended as far as the aortic bifurcation, the duration of the procedure might be prolonged by 1 h without increasing the incidence of complications.

CQ 9: What are the risk factors for postoperative recurrence? CQ 10: What are the patterns of recurrence following radical surgery?

Answer

Following radical cystectomy, isolated local recurrence and local recurrence in association with distant metastases are each seen in 10% of patients. Isolated local recurrence usually occurs within 2 years postoperatively, but can also occur after 5 years or more. The relationship with the number and extent of lymph node resection is unclear. Multidisciplinary therapy is needed for local recurrence, although the response is often poor.

Explanation

Local recurrence is seen in 20% of patients following radical surgery, with approximately half each as isolated local recurrence and at the same time as distant metastases. The reported frequency of isolated local recurrence is 12.5% (range, 5.0–33.8%).68,73–76 Known risk factors for local recurrence include pathological stage, lymph node metastases,68,74–77 the status of the surgical margins of the resected specimens and the histological findings of the primary tumor. Stratifying for the pathological findings, the local recurrence rate is 3–6% for pT2N0 and lower grade lesions, and 11–16% for pT3N0 and higher disease,68,74,75 increasing to 13–20% if lymph node metastases are present. The influence of the number of lymph nodes resected and the extent of lymphadenectomy on the local recurrence rate is unclear.

Known risk factors for distant metastasis include pathological findings of the primary tumor, lymph node metastases, and the status of the surgical margins, with the number of lymph nodes resected also playing a part.74–76

CQ 11: What are the indications for urethrectomy?

Answer

The indications for urethrectomy, with a view to an ileal neobladder or other form of continent urinary tractreconstruction, are tumor in the anterior urethra and the presence of neoplastic changes on intraoperative rapid pathological assessment of the urethral resection margin at radical cystectomy. (Grade of recommendation B.)

Explanation

In a study of 3165 patients since 1990, urethral recurrence was seen in 8.1% of patients following radical cystectomy.78 Known risk factors for urethral recurrence include multiple tumors, concomitant urothelial cancer and neoplastic changes in the bladder neck region or prostatic urethra.59,79 Stein et al. identified neoplastic changes (muscle-invasive bladder cancer or NMIBC) in the prostatic urethra, and urinary tract diversions (continent or non-continent) as independent risk factors for urethral recurrence.80 In another study, the histological depth of invasion of the resected primary tumor, neoplastic changes (NMIBC) in the prostatic urethra and a history of NMIBC were identified as risk factors for urethral recurrence.81 There is no question that in men, tumor in the prostatic urethra is a risk factor for urethral recurrence. However, differing results have been reported concerning the influence on recurrence by muscle-invasive versus NMIBC.80,81

The absolute indications for urethrectomy, with a view to ileal neobladder or other form of continent urinary tract reconstruction, are tumor in the anterior urethra and the presence of neoplastic changes on intra-operative rapid pathological assessment of the urethral resection margin at radical cystectomy.79,80

CQ 12: What are the indications for nerve-sparing radical surgery, and what are the functional results?

Answer

Although there are no firm indications of nerve-sparing radical surgery for muscle-invasive bladder cancer, in general it is indicated that nerve sparing can be considered if it does not impair the chances of a curative operation. Nerve preservation makes it easier to maintain urinary continence (in the case of continent urinary tract reconstruction) and erectile function. (Grade of recommendation B.)

Explanation

Schöenberg et al. performed nerve-sparing procedures when there was no macroscopic invasion of the lateral ligaments, finding that the results compared favorably with non-nerve-sparing procedures.73 On the other hand, Kessler et al. performed bilateral nerve-sparing procedures only in patients with bladder cancer located in the dome or anterior wall, or multiple NMIBC, and performed unilateral nerve-sparing procedures if a tumor was present only on the contralateral lateral ligament. They found no difference in the local recurrence rate between nerve sparing and non-nerve-sparing procedures.82

Kessler et al. found that daytime continence was achieved more quickly, and erectile function returned more quickly and in more patients, following nerve-sparing surgery.82 In women undergoing continent urinary tract reconstruction, normal urinary function was more easily achieved with nerve-sparing surgery, and the proportion of patients requiring auto-catheterization was significantly higher following non-nerve-sparing procedures.83

Seminal vesicle and prostate-sparing surgery (preserving the seminal vesicles, ductus deferens and prostate) is indicated in relatively young male patients with T2 or lower grade disease. Recovery of urinary continence (daytime continence: 97%; nocturnal continence: 95%) and erectile function (maintenance of potency: 82%) was more reliably achieved with such procedures.84

CQ 13: What are the indications for the different urinary tract diversion and reconstruction techniques?

Answer

Urinary tract diversion and reconstruction procedures do not affect oncological outcomes. The patient's social and medical background factors (including concurrent conditions and performance status) should also be considered, and selection of the technique to be used should therefore be made after thorough consultation with the patient. At present, ileal conduit diversion is the standard urinary tract diversion procedure, but the possibility of a continent neobladder reconstruction procedure using a section of bowel should also be pursued when there are no neoplastic changes in the urethra. (Grade of recommendation B.)

Explanation

The most commonly used urinary tract diversion procedures in Japan are cutaneous ureterostomy, ileal (colonic) conduit diversion, continent urinary reservoir construction and neobladder reconstruction using a bowel segment.

Cutaneous ureterostomy, a quick and simple procedure, is indicated in patients with concurrent conditions or other factors that make them a poor surgical risk for neobladder reconstruction using a bowel segment.

Ileal conduit diversion is the standard technique for non-continent urinary tract diversion. The frequency of early complications for this procedure is rather high, even if serious complications are uncommon. A variety of late complications can also occur, emphasizing the need for long-term follow up. Continent procedures include continent urinary reservoir construction and neobladder reconstruction using a bowel segment, with the latter recently becoming far more common. Ileal neobladder reconstruction is widely performed, typically using the Studer or Hautmann technique.85,86

CQ 14: What are the merits and demerits of continent urinary tract diversion procedures?

Answer

An ileal segment is often used in continent urinary tract diversion procedures, and an ileal neobladder potentially provides nearly normal urinary continence and urinary function. Although these reconstruction procedures do not affect oncological outcomes, good long-term results require meticulous follow up. (Grade of recommendation B.)

Explanation

An ileal segment is often used in continent urinary tract diversion procedures, although colonic segments are sometimes used. The benefits of continent urinary tract diversion procedures using an ileal segment (ileal neobladder) include the possibility of almost normal urinary continence and urinary function, and a positive body image.

Potential problems with the oncological outcome are urethral recurrence and local (intrapelvic) recurrence. Reported urethral recurrence rates are 1.5% with the Studer technique and 5.0% with the Hautmann technique.80,85,86 There is no established method for early detection of urethral recurrence and no set intervals between follow-up examinations. Hautmann stated that the initial manifestation of urethral recurrence is usually microscopic hematuria or altered urine flow. The local recurrence rate with the Hautmann technique is 10%, with ileal neobladder function affected in only 1.4%.85

Daytime urinary continence is achieved in 90% of patients with continent urinary tract diversion procedures, dropping to 70% for nocturnal continence. Voiding difficulties (urinary retention) are seen in 5–10% of males85,87,88 that tend to increase over time.85,88 The proportion of female patients with voiding difficulties increases over time, reaching 50% after 5 years.85

The reported incidence of upper urinary tract disorders such as hydronephrosis is 3% in recent patients.85,86 Surgery to prevent urine reflux increases the risk of stenosis of the uretero-ileal anastomosis and is considered unnecessary. Metabolic disturbances, in the form of electrolyte abnormalities or metabolic acidosis, sometimes occur in the immediate postoperative period, but the incidence of late onset hyperchloremic acidosis requiring treatment is low.85,86

Some are of the opinion that continent urinary tract diversion procedures do not contribute to improved patient quality of life (QOL). No studies have demonstrated clear superiority for any one urinary tract diversion or reconstruction technique in terms of QOL.

CQ 15: What are the merits and demerits of perioperative chemotherapy?

Answer

Perioperative chemotherapy might improve the therapeutic results for muscle-invasive bladder cancer. Preoperative and postoperative chemotherapy have their respective merits and demerits. At present, a definite improvement in survival rates has been shown only for preoperative cisplatin-based combination chemotherapy. (Grade of recommendation A.)

Explanation

The reported 5-year survival rate following radical cystectomy for pT2 disease is 70–80%, but decreases markedly for locally advanced pT3 or higher grade disease. There is no doubt that perioperative chemotherapy is the key to improving therapeutic results in patients with muscle-invasive bladder cancer.

A study conducted by the European Organization for Research and Treatment of Cancer and the Medical Research Council (EORTC/MRC) reported better 5-year survival rates with radical cystectomy plus CMV (cisplatin, methotrexate and vinblastine) chemotherapy than with radical cystectomy alone (or radiation monotherapy).89 A clinical trial conducted by the Southwest Oncology Group (SWOG) Intergroup also showed prolonged survival timesfor patients with locally advanced bladder cancer treated with MVAC chemotherapy plus radical cystectomy compared with radical cystectomy alone.90

A meta-analysis found that preoperative cisplatin-based combination chemotherapy improves the overall survival rate by 5%, and the recurrence-free rate by 9%.91 Although postoperative chemotherapy is assumed to have some effect, a lack of appropriate clinical trials has prevented any conclusions being reached.92 Although some benefits have been shown with preoperative chemotherapy, it is unclear which combination of anticancer agents is most effective. MVAC chemotherapy is the standard treatment for urothelial cancers. However, it is unclear whether the efficacy seen with GC (gemcitabine and cisplatin) chemotherapy in the treatment of advanced urothelial cancers with metastases can be reproduced as preoperative chemotherapy.93

CQ 16: What are the complications of radical surgery plus urinary diversion?

Answer

A variety of possible complications are associated with each urinary diversion procedure, necessitating vigorous long-term follow up.

Explanation

Following a successful tubeless cutaneous ureterostomy procedure, catheterization is rarely necessary, although stomal stenosis occurs in 50% of cases.94 Peristomal skin irritation is also common, and serious complications include impaired renal function and urolithiasis associated with repeated urinary tract infections. A tubeless condition is achieved in 80–90% of cases using the Toyoda95 and Hirokawa96 techniques.

More reports of complications of ileal conduit diversion procedures have emerged as the number of patients under long-term follow up increases. Maderbacher et al. reported complications in 66% of patients in a long-term follow-up survey related to kidney function/morphology in 27%, stoma in 24%, bowel in 24%, symptomatic urinary tract infections in 23%, stenosis of the conduit/ureteral anastomosis in 14% and urolithiasis in 9%.97 Late complications include stenosis of the anastamosis between the ureter and neobladder in 2.0–9.3%, and vesicoureteric reflux (VUR) in 3.3%. Other complications include abdominal wound herniation in 3.8–4.6%, lymphocele in 2.0–2.7%, and acidosis in 1.1–4.4%. Vitamin B12 deficiency is reported in 13.6–16.6% of patients due to diversion of a portion of the ileum.

CQ 17: Is radical surgery feasible in older patients?

Answer

Total cystectomy is recommended for older patients with good performance status (PS) and no serious pre-existing conditions. (Grade of recommendation B.)

Explanation

With recent advances in surgical and anesthetic techniques, no difference is seen in perioperative mortality rates attributable to age, and it is important to consider the balance between aiming for a cure and quality of life (QOL). There have been few reports with large series of older patients, although Souli et al. reported early complications typical for older patients, including prolonged ileus in 12.3%, pyelonephritis in 12.3%, delirium in 10.9% and pneumonia in 8.2%, in their study of patients aged over 75 years undergoing radical cystectomy.98 Clark et al. compared the incidence of urinary diversion-related complications in patients aged <70 and ≥70 years undergoing ileal conduit diversion or neobladder reconstruction procedures, finding no differences in the rates of perioperative (within 30 days after surgery) mortality, early (<90 days after surgery) complications, early diversion-related complications or late (≥90 days after surgery) complications.72

In their comparison of cutaneous ureterostomy and ileal conduit diversion procedures in patients aged ≥75 years with high ASA scores, Deliveliotis et al. reported high rates of perioperative, early and late complications with ileal conduit diversion procedures, supporting the benefits of cutaneous ureterostomy procedures in high-risk older patients.99

V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ1: What are the indications for total cystectomy for stage IV bladder cancer and surgery for metastases?

Answer

Radical cystectomy is indicated when disease is confined to the pelvis and a very good tumor shrinking response can be expected from chemotherapy ± radiotherapy. (Grade of recommendation B.)

Explanation

For T4bN0M0 or anyTN1-3M0 disease, when preoperative chemotherapy ± radiotherapy has shrunk extravesical lesions to the extent that they are almost undetectable, then total cystectomy with lymphadenectomy can be expected to contribute to an improved survival.90 However, it is unclear whether survival will in fact be prolonged in these patients over what can be expected with a more conservative approach.

Similarly for anyTN1-3M0 disease, if total cystectomy with lymphadenectomy can be expected to provide clear surgical margins, then total cystectomy followed by postoperative chemotherapy can be expected to provide improved survival.100–102

On the other hand, for anyTanyNM1 disease, with metastases to the liver or lung, even if a CR is achieved with initial chemotherapy, surgical resection of metastatic lesions cannot be recommended. This is because we must assume that widespread microscopic dissemination of tumor cells has already occurred.

CQ 2: Is urinary diversion indicated in patients with advanced bladder cancer?

Answer

Cutaneous ureterostomy, and rarely ileal conduit diversion, can be performed as an isolated procedure in patients in whom overall tumor control can be expected, and renal failure secondary to hydronephrosis would be a dominant factor adversely affecting QOL and life expectancy. (Grade of recommendation B.)

Explanation

Cutaneous ureterostomy or another urinary tract reconstruction procedure can be considered as an isolated procedure when the urinary tract is occluded distal to the lower portion of the ureter by local progression within the pelvis, and no relief can be expected with chemotherapy ± radiotherapy. The aim is to prevent incipient mortality from postrenal renal failure.

VI. Systemic chemotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ 1: Which is more useful in the treatment of metastatic and recurrent bladder cancer, the MVAC or GC chemotherapy regimen?

Randomized comparative trials of the MVAC and GC chemotherapy regimens, with overall survival (OS) as the endpoint, found similar therapeutic effects for the two regimens. Reported adverse events including neutropenia, stomatitis and alopecia were milder with the GC regimen. (Grade of recommendation A.)

Explanation

RCT of the MVAC and GC chemotherapy regimens in the treatment of bladder cancer found similar results for the two regimens in all parameters of efficacy: overall survival, time to progression, time to failure and response rate.93,103 There were no cases of grade 3 or 4 adverse events including neutropenia, stomatitis or alopecia in the GC group, and the GC regimen was also superior in terms of QOL parameters, including weight, PS and malaise.103 In Western countries, the GC regimen is in the process of replacing the MVAC regimen as first-line chemotherapy for bladder cancer. A Phase II trial has been conducted in Japan104 and gemcitabine has been approved for medical insurance cover, and therefore it is likely that the GC regimen will also replace the existing MVAC regimen as first line in Japan as well. The 2008 NCCN Guidelines recommend GC chemotherapy as the treatment of first choice.

CQ 2: What chemotherapy regimens with new anticancer agents are available for the treatment of bladder cancer?

Answer

A number of clinical trials are under way with chemotherapy regimens containing combinations of agents such as cisplatin, taxans (paclitaxel or docetaxel), gemcitabine and ifosfamide.

At present, no large-scale RCT have yielded therapeutic results superior to the MVAC or GC regimens, although we expect a lot from future studies. We also await with anticipation the results of clinical trials of new targeted chemotherapy agents. (Grade of recommendation C.)

Explanation

The PCG (paclitaxel, cisplatin and gemcitabine) regimen adds paclitaxel to the GC regimen to increase its antitumor effect. A large-scale RCT comparing PCG and CG chemotherapy found a better response rate (RR) for the former, but no significant differences in progression-free survival (PFS) or OS.105

A Phase II trial of trastuzumab, a monoclonal antibody to human epidermal growth factor receptor-2/neu (HER2/neu) in combination with paclitaxel, carboplatin and gemcitabine yielded promising results, with an RR of 70% and median OS of 14.1 months in patients with HER2-positive urothelial cancers.106

CQ 3: What chemotherapy regimens can be used when there are problems with cardiac, pulmonary or renal function?

Answer

Measures such as substituting carboplatin for cisplatin and regimens containing hepatically metabolized taxans or gemcitabine are used, but patient numbers are small and no formal evaluations have been made. (Grade of recommendation C.)

Explanation

Cisplatin-based chemotherapy regimens are the standard treatment for urothelial cancers; at least one patient in three is unable to undergo this treatment due to adverse events, including renal toxicity.107 Carboplatin is considered to have less renal toxicity or neurotoxicity, but weaker antitumor activity, than cisplatin.

CQ 4: What prognostic factors are known for outcomes in patients with recurrent and metastatic bladder cancer?

Answer

A number of studies have identified performance status (Karnofsky performance status (KPS) <80%) and metastases to distant organs (e.g. lung, liver and bone) as prognostic factors that influence chemotherapy RR and survival rates. Other prognostic factors include hemoglobin and alkaline phosphate levels and the number of metastases. (Grade of recommendation B.)

Explanation

A study of patients with inoperable or metastatic urothelial cancer identified a KPS <80% and distant metastases, to the lung, liver and bone, as factors that influence outcomes.108 A study comparing MVAC and GC chemotherapy regimens also reported a strong correlation in both treatment groups between outcomes and the following factors: KPS ≥80% and metastases to distant organs.103 From the above reports, we can see a trend towards common, fixed prognostic factors for chemotherapy for inoperable or metastatic urothelial cancer, irrespective of the regimen used.

VII. Radiotherapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

CQ 1: What is the place of radiotherapy in the treatment of bladder cancer?

Answer

Radical radiotherapy is performed for muscle-invasive bladder cancer with the aim of bladder preservation. Symptomatic radiotherapy is performed with the aim of alleviating symptoms, such as pain and hematuria, related to bone metastasis or local invasion. (Grade of recommendation B.)

Explanation

Radiotherapy is not part of the standard treatment for NMIBC. However, chemoradiotherapy has been trialed in patients with high-grade T1 NMIBC, with favorable results.

The standard treatment for muscle-invasive bladder cancer is total cystectomy. Bladder-preserving therapy, a combination of TURBT, chemotherapy and radiotherapy, is possible in some patients with muscle-invasive bladder cancer, without decreasing the survival rate.62,63,65

The ideal indication for bladder-preserving therapy for muscle-invasive bladder cancer is a single small-diameter tumor with T2 or T3 clinical staging.63 Strict indications for bladder-preserving therapy are yet to be established; however, and within the abovementioned triple combination therapy, a number of different treatment regimens exist.

For patients unable to undergo chemotherapy due to renal impairment or advanced age, radiation monotherapy is an option, although the therapeutic results are often less than satisfactory.

CQ 2: What is the optimum timing and effect for combination chemotherapy and radiotherapy in patients with stage II and III bladder cancer?

Answer

No definite conclusions have been reached concerning the timing of combination chemotherapy and radiotherapy.

Explanation

Cisplatin-based chemotherapy regimens can be expected to amplify the local effects of radiotherapy and the combination to suppress distant metastases. However, we have not reached the stage of determining the optimum timing.

Chemotherapy regimens include monotherapy with cisplatin, a radiation-sensitizing agent or multiple agents. Irradiation of the bladder cancer usually follows a conventional fractionation schedule, with a dose per fraction of 2 Gy. Considering the radiation tolerance of the bladder, the total radiation dosage is generally 60–60 Gy. This multidisciplinary treatment yields CR rates of 70–80%, 5-year survival rates of 50–70% and 5-year cancer-specific survival rates of 60–80%.62,63,65

CQ 3: What are the indications, optimum dosage and fractionation schedule for radiotherapy as part of bladder-preserving therapy for stage II and III bladder cancer?

Answer

Bladder-preserving therapy, a combination of TURBT, chemotherapy and radiotherapy, is possible in somepatients with muscle-invasive bladder cancer that is clinical stage T2 or T3 disease, and a small number of tumors that are small in size. The standard schedule administers up to 40–50 Gy using a fourfold technique, including the pelvic lymph nodes, then confines to the bladder up to 60–70 Gy. The standard dose per fraction is 1.8 or 2.0 Gy/day. (Grade of recommendation B.)

Explanation

Bladder-preserving therapy first involves TURBT, resecting as much tumor as possible, followed by chemoradiotherapy (simultaneous chemotherapy and radiotherapy).62

No Phase III studies comparing conventional fractionation schedules with other schedules (hyperfractination, hypofractination) in the treatment of bladder cancer have been conducted, so the influence of the fractionation schedule on the therapeutic results is yet to be elucidated. A meta-analysis of the relationship between radiation dosage and local control rates identified a dose-response relationship with bladder cancer, with the 3-year local response rate increasing 1.44–1.47 times with a 10 Gy increase in the total dose.109 Intensity modulated radiation therapy (IMRT), and particle beam therapies such as proton therapy, have been trialed in the treatment of bladder cancer as attempts to increase the radiation dosage. A 5-year survival rate of 66% was reported with proton therapy,63 and the challenge will now be to demonstrate its superiority over radiotherapy using high-energy X-rays with 2-D or 3-D planning.

CQ 4: What are the indications, optimum dosage, fractionation schedule and results for radical radiotherapy for stage II and III bladder cancer?

Answer

Radical radiotherapy includes both radiation monotherapy and adjuvant radiotherapy following TURBT, with the aim of bladder preservation. Radiation monotherapy is offered to patients unable to undergo chemotherapy due to renal impairment or advanced age. Radiation monotherapy with a total radiation dosage of 60–66 Gy, a conventional fractionation schedule, and a dose per fraction of 2 Gy, yields 5-year survival rates of 60–80% for T1 disease, 30–60% for T2 and 20–40% for T4. (Grade of recommendation B.)

Explanation

A clinical study of radical radiotherapy in the treatment of invasive bladder cancer compared the efficacy of hyperfractionation with irradiation three times a day with conventional fractionation.110 A meta-analysis showed efficacy for hyperfractionation, but no enhancement of therapeutic results was seen in a Phase III trial. Therefore, at present, conventional fractionation schedules are the standard treatment. The 5-year survival rates with radical radiation monotherapy are inferior to those achieved in combination with chemotherapy.111

CQ 5: In what situations is radiotherapy effective as palliative therapy?

Answer

Radiotherapy is effective not only as radical therapy, but also for the purpose of alleviating symptoms. Radiotherapy is indicated, and effective, in the treatment of symptoms of muscle-invasive bladder cancer, both pain and hematuria associated with local progression, and symptoms associated with distant metastases, including bone or lymph nodes. (Grade of recommendation B.)

Explanation

Radiotherapy can be effective in treating symptoms associated with local progression of bladder cancer, retarding disease progression even when an inoperable or locally advanced tumor cannot be completely covered by the treatment field, or a curative radiation dose cannot be administered. Radiotherapy can also alleviate tumor-related pain and pressure, and control hematuria associated with tumor hemorrhage. For symptoms associated with distant metastases, including bone or lymph nodes, radiotherapy can alleviate the symptoms of painful bone metastasis, and emergency irradiation is an effective treatment for transverse spinal cord syndrome due to malignant spinal cord compression. Radiotherapy is also effective in treating cerebral metastases, relatively uncommon with bladder cancer, and good long-term survival has been reported, in particular, in cases with a single cerebral metastasis and no other distant metastases.112 Unlike radical radiotherapy, palliative radiotherapy for bladder cancer can be administered with a hypofractionation schedule, completing the course more quickly using a larger dose per fraction, out of consideration for the patients' general condition and prognosis. Various hypofractionation schedules, such as 8.5 Gy in two fractions over 3 days and 3 Gy in 10 fractions over 2 weeks, have been trialed for not only bone metastasis but also lesions localized to the bladder. Similar therapeutic effects are achieved over a shorter period than with conventional fractionation, but caution is required as hypofractionation has been reported to cause more early side-effects, including cystitis and acute gastrointestinal reactions.113

CQ 6: What are the indications, dosage and results for radiotherapy for bone metastasis?

Answer

Radiotherapy is widely used in the treatment of bone metastasis, irrespective of the site of the primary cancer, and is highly effective in alleviating symptoms. In short-term radiotherapy, sometimes only one fraction is used, and has been confirmed to be as effective as conventional fractionation schedules. Retreatment for recrudescence of pain and post-treatment pathological fractures are significantly more frequent with single fraction therapy; however, a conventional fractionation schedule should be applied when the patient can be expected to survive for a reasonable period. (Grade of recommendation B.)

Explanation

Radiotherapy is an important treatment modality for pain associated with bone metastasis that is inadequately controlled with analgesia, and also for neurological symptoms associated with metastatic lesions and for transverse spinal cord syndrome due to malignant spinal cord compression. The standard course is 30 Gy in 10 fractions over 2 weeks, but a comparative trial that evaluated the efficacy of a shorter treatment course found no difference in pain alleviation between 20 Gy in 5 fractions over 1 week and a single 8 Gy fraction.114 A Phase III trial comparing 30 Gy in 10 fractions over 2 weeks and a single 8 Gy fraction also found no difference in efficacy.115 However, a systematic review that analyzed clinical trials comparing single fraction with conventional fractionation therapy found no difference in pain alleviation, but significantly more frequent retreatment for recrudescence of pain and post-treatment pathological fractures with single fraction therapy.116 A conventional fractionation schedule should therefore be applied when there are no other active metastases, and the patient can be expected to survive for a relatively long time. Hemibody irradiation has been trialed for cases of multiple bone metastasis with multiple painful lesions, with reported ≥90% pain alleviation.117

In these cases also, short course treatments such as 15 Gy in five fractions over 5 days or 12 Gy in four fractions over 2 days, are effective.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Evidence for these Guidelines
  5. I. Epidemiology and diagnosis ()
  6. II. Treatment of NMIBC
  7. III. Treatment of CIS
  8. IV. Diagnosis and treatment of Stage II (T2a, b N0 M0) and Stage III (T3a, b N0 M0) bladder cancer
  9. V. Diagnosis and treatment of Stage IV (T4b N0 M0, anyT N1-3 M0, anyT anyN M1) bladder cancer
  10. VI. Systemic chemotherapy
  11. VII. Radiotherapy
  12. References
  13. Appendix

Appendix I

Evidence-based clinical practice guidelines for Bladder Cancer Committee

Committee chairman

Hideyuki Akaza

Professor, Department of Urology and Andrology

Graduate School of Comprehensive Human Sciences, Tsukuba University

Committee

Osamu Ogawa

Professor, Department of Urology

Graduate School of Medicine, Kyoto University

Hiroyuki Nishiyama

Associate Professor, Department of Urology

Graduate School of Medicine, Kyoto University

Jun Watanabe

Assistant Professor, Department of Urology

Graduate School of Medicine, Kyoto University

Seiichiro Ozono

Professor, Department of Urology

Hamamatsu University School of Medicine

Hiroshi Furuse

Assistant Professor, Department of Urology

Hamamatsu University School of Medicine

Tsuneharu Miki

Professor, Department of Urology

Kyoto Prefectural University of Medicine

Yoichi Mizutani

Associate Professor, Department of Urology

Kyoto Prefectural University of Medicine

Taiji Tsukamoto

Professor, Department of Urologic Surgery and Andrology

Sapporo Medical University School of Medicine

Naoya Masumori

Associate Professor, Department of Urologic Surgery and Andrology

Sapporo Medical University School of Medicine

Tomoaki Fujioka

Professor, Department of Urology

Iwate Medical University School of Medicine

Wataru Obara

Assistant/Instructor, Department of Urology

Iwate Medical University School of Medicine

Kenichi Tobisu

Shizuoka Cancer Center

Seiji Naito

Professor, Department of Urology

Graduate School of Medical Science, Kyushu University

Akira Yokomizo

Instructor, Department of Urology

Graduate School of Medical Science, Kyushu University

Tetsuo Akimoto

Associate Professor, Department of Radiology

Tokyo Women's Medical University

Evaluation committee

Tadao Kakizoe

President Emeritus, National Cancer Center

President, Japan Cancer Society

Nagahiro Saijo

Professor, Department Medical Oncology

Kinki University School of Medicine

Masahiro Hiraoka

Professor, Therapeutic Radiology and Oncology

Kyoto University Graduate School of Medicine

Organizer

Shiro Hinotsu

Associate Professor, Department of Pharmacoepidemiology

Graduate School of Medicine and Public Health, Kyoto University

Naoto Miyanaga

Assistant Professor, Department of Urology

Graduate School of Comprehensive Human Sciences, Institute of Clinical Medicine University of Tsukuba