Essential content of evidence-based clinical practice guidelines for bladder cancer: The Japanese Urological Association 2015 update
Abstract
The Japanese Urological Association revised the clinical practice guidelines for bladder cancer in April 2015. This was the first update carried out in the 6 years since the development of the initial clinical practice guidelines for bladder cancer in 2009. The descriptive content was revised, and additions were made with a focus on new-found evidence and advances in the latest medical practices, and on the basis of the increasingly aging population observed in the underlying social context in Japan. An algorithm for the treatment of bladder cancer has been presented as a new trial. In the present article, we will introduce the essential contents and clinical questions that address the present revisions.
Abbreviations & Acronyms
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- BCG
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- bacillus Calmette–Guérin
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- CIS
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- carcinoma in situ
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- CQ
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- clinical question
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- TURB
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- transurethral resection of a bladder tumor
Introduction
The Japanese Urological Association revised the clinical practice guidelines for bladder cancer in April 2015 with the support of the Japanese Society for Radiation Oncology. This was the first update carried out in the 6 years since the first edition of the clinical practice guidelines for bladder cancer was published in 2009.1 The new revised guidelines essentially follow the style of the first edition. While referring to the National Comprehensive Cancer Network and European Association of Urology guidelines, revisions were made taking into account new evidence over these past 6 years, items that strengthened evaluations, advancements in the latest medical practices and trends in medical practices in the field of urological treatment in Japan.
The risk classification has been clarified with respect to non-muscle-invasive bladder cancer. Furthermore, given the underlying social context in Japan with the increasingly aging population, there is greater mention of treatment for elderly patients. As a new trial, an algorithm for the treatment of bladder cancer has been presented to ease the understanding of all aspects of the medical treatment system. In the present article, we will focus on the essential content and CQs that address the present revisions.
In the present article, we have cited particularly important CQs and remarks that were changed in this revision, or came to receive attention recently in the field of urological treatment in Japan.
Circumstances leading up to the revisions with references, recommended grade and evidence level
In 2012, the Japanese Urological Association established a committee, consisting of urologists and radiologists, that was responsible for the development of guidelines (Appendix). The new revised guidelines follow the style of the first edition of the bladder cancer clinical practice guidelines in 2009, while referring to the renewed National Comprehensive Cancer Network and European Association of Urology guidelines. In principle, the revisions were made taking into account new evidence from the past 6 years, and advances in the latest medical practices given Japan's social context of an increasingly aging population. Initially, 48 CQs were created. Key words for each CQ were subsequently created, and a literature search was carried out with the cooperation of the Japanese Medical Library Association. Literature deemed by committee members as containing important evidence was examined for validity by the committee and incorporated. The grade of the recommendation and the evidence level in the present manuscript were determined in accordance with the Handbook for Clinical Practice Guideline Development (Table 1). However, in the event that decisions had to be made using low-level evidence, the recommended grades were determined, reflecting deliberations and resulting in agreement between committee members.
| Five grades of recommendations from A to D were set based on agreement among the members of the committee for establishment of Clinical Practice Guidelines for Bladder Cancer: |
| A. Strongly recommended for implementation in routine clinical practice, because there is sufficient evidence |
| B. Recommended for implementation in routine clinical practice, because there is some evidence |
| C1. Might be implemented in routine clinical practice, although there is insufficient evidence |
| C2. Not recommended for implementation in routine clinical practice, because there is insufficient evidence |
| D. Not recommended for implementation in routine clinical practice, because there is evidence that it might be harmful to patients |
Epidemiology
In 2008, the age-adjusted prevalence of bladder cancer in Japan was 7.2 (/100 000 individuals per year), which according to sex was 12.8 for men and 2.8 for women, showing an approximately fourfold incidence for men over women. The age-adjusted death rate according to the 2012 tabulation was 2.1 (/100 000 individuals per year) for both men and women (men 3.6, women 1.0). A strong correlation has been noted between smoking and the prevalence of bladder cancer. Data analysis of the Japanese Urological Association bladder cancer registry showed that the onset age of bladder cancer is 5–6 years earlier in smokers than non-smokers.2
Diagnosis
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- CQ4
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- Is cystoscopy useful for the diagnosis of bladder cancer?
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- Answer
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- Cystoscopy is recommended for all patients who show symptoms suggestive of bladder cancer (grade of recommendation: A).
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- CQ5
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- What is the proper way to diagnose clinical T staging?
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- Answer
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- TURBT is required to accurately diagnose muscular invasion. Furthermore, in the event of T1 high-grade cancer, a second transurethral resection is recommended (grade of recommendation: A).5, 6 Image diagnosis and assessment are carried out mainly with magnetic resonance imaging (grade of recommendation: B).7
Therapeutics
The treatment plan for bladder cancer should be determined based on accurate diagnosis. To achieve this, TURBT, including muscular components, is necessary.8 The treatment concept for non-muscle-invasive bladder cancer and CIS (stage 0, I) entails bladder preservation. The extent of the control of recurrence and progression is extremely important. Abundant evidence has emerged from Japan regarding the effects of intravesical infusion therapy.9, 10 In contrast, it is also important not to be too particular about preservation and miss the timing of total cystectomy.11
For muscle-invasive bladder cancer (stages II and III) localized to the bladder without metastasis, total cystectomy + pelvic lymphadectomy + urinary diversion is the standard treatment option, and to improve the outcomes, trials have been carried out using perioperative combination chemotherapy with multimodal therapy.12 In the 2015 version, laparoscopic and robot-assisted surgeries reported recently were addressed as the novel choices.13, 14
Treatment of bladder cancer with metastasis (stage IV) is based on systemic chemotherapy with the aim of prolonging survival; however, in some cases, surgical treatment effectively improves prognosis and eases symptoms. Furthermore, radiotherapy also effectively relieves symptoms, and a combination of these treatments is used to improve quality of life. Aggressive treatment is difficult for many patients. In such cases, an appropriate treatment strategy should be selected to ease symptoms and improve quality of life.
An algorithm based on the aforementioned concept has been proposed for the treatment of bladder cancer (Fig. 1).
Treatment of non-muscle-invasive bladder cancer
The present guidelines follow the risk classification for non-muscle-invasive bladder cancer proposed in the guidelines published in 2009 (Table 2).1 The basic treatment plan is determined according to the risk classification. In all cases, a single injection of an anticancer agent is given during initial TURBT. Only a single injection is recommended for the low-risk group, whereas a choice of maintenance infusion of an anticancer agent or BCG for the intermediate-risk group and BCG maintenance infusion or total cystectomy for the high-risk group is recommended (Fig. 1). In the 2015 version, BCG maintenance infusion was recommended for not only the high-risk group, but also the intermediate-risk group based on the results from the European Organization for Research and Treatment of Cancer study.15 Furthermore, the term BCG-failure is divided into four categories based on the proposal of Nieder et al., comprising BCG-refractory, BCG-resistant, BCG-relapsing and BCG-intolerant.16
| Low-risk group |
| Single lesion, primary lesion, <3 cm, Ta, low grade and no concurrent CIS are all satisfied |
| Intermediate-risk group |
| Low grade, no concurrent CIS and multiple lesions or lesion size of >3 cm |
| High-risk group |
| Including any of the following: T1, high grade, CIS (including concurrent CIS), multiple recurrence |
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- CQ18
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- Is there a recommended time to perform total cystectomy for high-risk muscle-non-invasive bladder cancer?
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- Answer
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- For patients with high-risk muscle-non-invasive bladder cancer, high progression risk and who are BCG-refractory, total cystectomy is recommended (grade of recommendation: B).
Treatment of CIS
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- CQ21
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- For CIS patients who relapse following BCG therapy, is second-line BCG therapy recommended?
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- Answer
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- Although total cystectomy is the recommended treatment for CIS patients who develop recurrence following BCG therapy, second-line BCG therapy is an option in patients for whom total cystectomy is difficult, and in patients in whom a period of more than a year has elapsed before recurrence (grade of recommendation: C1).
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- CQ22
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- Is there a recommended time to perform total cystectomy for CIS?
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- Answer
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- The recommended time to perform total cystectomy for CIS is when BCG therapy, including second-line therapy, has been deemed a failure. Furthermore, in patients with CIS located in the prostatic urethra, total cystectomy should be performed immediately (grade of recommendation: B).
Stage II and stage III treatment
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- CQ27
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- What is the follow up after total cystectomy for stage II and stage III patients?
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- Answer
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- Observation items for the follow up after total cystectomy for muscle-invasive bladder cancer includes: (i) cancer recurrence (localized, urethral, upper urinary tract and distant metastasis; (ii) changes in the upper urinary tract associated with urinary diversion; (iii) renal function; and (iv) metabolic disorder. Although there is no established interval between carrying out each test, they are recommended at least every 3–6 months in the 2 years after surgery and once a year thereafter. When setting these intervals, the degree of cancer malignancy and progression should be taken into consideration (grade of recommendation: C1).
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- CQ32
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- What is the clinical significance of extended lymphadectomy in total cystectomy?
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- Answer
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- Extending the range of lymphadectomy might improve the prognosis of muscle-invasive bladder cancer (grade of recommendation: C1).
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- CQ33
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- Can total cystectomy be recommended for elderly patients?
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- Answer
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- For elderly patients in good general condition without any concurrent disease, total cystectomy can be recommended in institutions with good experience (grade of recommendation: B).
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- CQ34
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- What are the indications for and who are the target subjects for bladder-preserving treatment?
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- Answer 1
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- On providing consent to be excluded from standard treatment, bladder-preserving treatment is carried out for patients who desire to preserve their bladders (grade of recommendation: C1).
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- Answer 2
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- The procedure is well suited for patients with localized cancer with an invasion depth of T3a or less, tumor diameter of ≤3 cm and no CIS or hydronephrosis (grade of recommendation: B).
Treatment for stage IV
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- CQ36
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- What are the indications for cystectomy in the treatment of stage IV bladder cancer?
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- Answer
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- When the lesion is confined within the pelvis, and marked cytoreduction is achieved with chemotherapy, an improved prognosis can be expected with a total cystectomy with pelvic lymphadectomy (grade of recommendation: C1).
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- CQ37
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- What are the indications for urinary diversion in the treatment of advanced bladder cancer?
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- Answer
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- In the event of ureteral obstruction resulting from cancer invasion, percutaneous nephrostomy is indicated with the aim of prolonging survival and enabling salvage therapy. In the event that long-term prognosis can be expected, cutaneous ureterostomy is also an option. Furthermore, percutaneous nephrostomy and cutaneous ureterostomy should also be considered to ease symptoms (grade of recommendation: C1).
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- CQ38
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- What are the indications for surgery to treat stage IV bladder cancer with metastatic lesions?
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- Answer
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- If the patient is carefully selected, resection of bladder cancer with metastatic lesions can prolong survival. Indications include primary lesions that can be completely resected, small lesions, slowly recurrent patients without rapid progression and patients who are sensitive to chemotherapy (grade of recommendation: C1).
Systemic chemotherapy
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- CQ39
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- For metastatic, recurrent bladder cancer, is methotrexate, vinblastine, doxorubicin and cisplatin therapy or gemcitabine plus cisplatin therapy more effective?
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- Answer
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- In a randomized controlled trial with overall survival as the end-point, it was reported that the therapeutic effects of the two treatments were equal. In terms of the toxicity profile, gemcitabine plus cisplatin therapy is better than methotrexate, vinblastine, doxorubicin and cisplatin therapy, and at present, gemcitabine plus cisplatin is the first-line therapy (grade of recommendation: A).24, 25
Radiotherapy
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- CQ45
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- Is radiotherapy combined with chemotherapy recommended for stage II and III cancers as bladder-sparing therapy?
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- Answer
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- Compared with radiotherapy alone, chemoradiation therapy yields better therapeutic results. Excluding patients with renal dysfunction and elderly patients who are unable to undergo combination chemotherapy, chemoradiation therapy is recommended (grade of recommendation: A).
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- CQ48
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- What are the indications, radiation dosage and effects of radiotherapy bone metastasis?
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- Answer
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- Radiotherapy is extensively carried out for bone metastasis irrespective of the primary site, and is highly effective for easing symptoms. Short-term irradiation, such as a single dose, can be administered, and it has been affirmed that there is no difference with normal fractionated irradiation in the pain-easing effect. Furthermore, internal radiotherapy using bone-seeking radioisotope preparations are another treatment option for multiple metastases (grade of recommendation: B).
Conflict of interest
These guidelines were developed to contribute to society. There are conflicts of interest because the committee members do engage in lecture activities with corporations. However, the recommendations given in these guidelines are based on scientific evidence, and are not influenced by the interests of specific organizations, manufactured goods or technologies. The expenses required to develop this guideline were financed by the Clinical Practice Guideline Development Fund of the Japanese Urological Association.
Appendix
Committee members of the Clinical Practice Guideline for Bladder Cancer – JUA 2015.
Chairperson: Yoshinobu Kubota (Emeritus Professor, Department of Urology, Yokohama City University Graduate School of Medicine). Committee members: Hiroyuki Nishiyama (Professor, Department of Urology, University of Tsukuba), Shiro Hinotsu (Professor, Center for Innovative Clinical Medicine, Okayama University Hospital), Osamu Ogawa (Professor, Department of Urology, Kyoto University), Keiji Inoue (Associate Professor, Kochi University Medical School), Seiichiro Ozono (Professor, Department of Urology, Hamamatsu University School of Medicine), Eiji Kikuchi (Associate Professor, Department of Urology, Keio University School of Medicine), Tsuneharu Miki (Professor, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine), Hideyasu Matsuyama (Professor, Department of Urology, Yamaguchi University Graduate School of Medicine), Tomoaki Fujioka (Emeritus Professor, Department of Urology, Iwate Medical University School of Medicine), Chikara Ohyama (Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Hiroyuki Fujimoto (Director, Urology Division, National Cancer Center Hospital), Haruhito Azuma (Professor, Department of Urology, Osaka Medical College), Tomonori Habuchi (Professor, Department of Urology, Akita University Graduate School of Medicine), Masayuki Nakagawa (Professor, Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University), Takashi Mizowaki (Associate Professor, Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine). Supporting committee members: Yoshiyuki Matsui (Associate Professor, Department of Urology, Kyoto University), Takashi Kobayashi (Assistant Professor, Department of Urology, Kyoto University), Kimito Osaka (Assistant Professor, Department of Urology, Yokohama City University Graduate School of Medicine), Hiroshi Furuse (Associate Professor, Department of Urology, Hamamatsu University School of Medicine), Yoshio Naya (Associate Professor, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine), Wataru Obara (Professor, Department of Urology, Iwate Medical University School of Medicine), Takuya Koike (Associate Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Takahiro Yoneyama (Assistant Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Yasuhiro Hashimoto (Associate Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Shingo Hatakeyama (Assistant Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Atsushi Imai (Assistant Professor, Department of Urology, Graduate School of Medicine, Hirosaki University), Hiroyuki Nakanishi (Associate Professor, Department of Urology, Graduate School of Medical Sciences, Kyoto Prefectural University of Medicine), Tomohiko Hara (Medical staff, Urology Division, National Cancer Center Hospital), Norihiko Tsuchiya (Associate Professor, Department of Urology, Akita University Graduate School of Medicine), Takamitsu Inoue (Associate Professor, Department of Urology, Akita University Graduate School of Medicine), Junichi Ohta (Director, Department of Urology, Yokohama Municipal Citizen's Hospital), Kotaro Suzuki (Director, Department of Urology, Saiseikai Yokohamashi Nanbu Hospital), Atsushi Fujikawa (Medical staff, Department of Urology, Ohguchi Higashi General Hospital), Susumu Umemoto (Department of Urology, Hiratsuka Kyousai Hospital), Koji Izumi (Department of Urology, Yokohama City University Graduate School of Medicine). Executive Office: Noboru Nakaigawa (Associate Professor, Department of Urology, Yokohama City University Graduate School of Medicine), Sumio Noguchi (Vice Director, Yokosuka Kyosai Hospital).
