On 25 February 2015, the National Institute for Health and Clinical Excellence (NICE, UK) updated its guidelines on the diagnosis and treatment of bladder.
Bladder cancer is the seventh most common tumour in the UK and is three to four times more common in men than women. The majority of cases are older than 60 years and the main risk factor is increasing age, with smoking and industrial chemical exposure also increasing the risk. Bladder cancer is often detected by visual or microscopic haematuria and is also often admitted to hospital as an emergency, with a poor prognosis.
Most bladder cancers do not involve the muscularis and usually require only transurethral resection of the bladder (TURBT), followed by intravesical chemotherapy or vaccination and then follow-up by cystoscopy, although those at high risk in this group require surgical removal of the bladder.
Cure should be the goal for those with muscular bladder involvement, with chemotherapy, cystectomy or radiotherapy, while those with advanced incurable disease may receive chemotherapy and radiotherapy. If the genitourinary tract is involved, treatment can have not only a physical but also a huge psychological impact on the patient.
The incidence and treatment of bladder cancer makes it one of the most costly tumours in the NHS (National Health Service in England) The management of bladder cancer in the NHS is highly variable and evidence suggests that patients with bladder cancer have a worse experience than those with other cancers. The guidelines apply to adults aged 18 years and over with suspected bladder cancer, newly diagnosed bladder cancer or recurrent bladder cancer (urothelial, adenocarcinoma, squamous or small cell carcinoma) or urothelial cancer.
There is a lack of good quality evidence to recommend the management of non-urethral epithelial bladder cancer (adenocarcinoma, squamous or small cell carcinoma). The guidelines do not apply to people under 18 years of age or to people with bladder sarcoma, uroepithelial carcinoma of the upper urinary tract or secondary bladder or urethral cancer (e.g. bowel or cervical cancer spreading to the bladder).
Medications
The guidelines assume that prescribers will use the summary of drug product characteristics to make treatment decisions with patients. Some of the drug indications recommended in the guidelines do not yet have market access in the UK. Prescribers are responsible for their decisions in accordance with professional guidelines. Written informed consent should be provided by the patient or their authorised person. Over-indication of medicines in the guidelines will be indicated in the corner of the recommendation note.
Patient-centred care
Guidelines provide advice on the best treatment for patients with bladder cancer and both patients and doctors have both the right and the responsibility to take into account individual needs and preferences. Patients should be given the opportunity to participate in decisions about their treatment and to work with their doctors to contribute to that treatment. Healthcare professionals are expected to comply with national regulations and legislation in the course of their medical practice.
Priorities for implementation
(1) Information about and support for patients with bladder cancer should be fully assessed at the point of diagnosis, when the first treatment is completed, when the disease recurs or progresses, when treatment changes and when palliative or end-of-life care needs to be discussed.
(2) Diagnosis
If tumour invasion of the muscularis is suspected on cystoscopy, CT or MRI should be performed for staging prior to TURBT.
Patients with suspected bladder cancer should undergo white light TUBRT and one of the following tests: photodynamic diagnosis, narrow spectrum imaging, cytology or urinary biochemical markers (e.g. UroVysion by FISH, ImmunoCyt, or nuclear matrix protein 22 assay [NMP22]). These should be performed or supervised by a TURBT experienced urologist.
A single intravesical mitomycin treatment is given to patients with suspected bladder cancer at the same time as the initial TURBT.
(3) Treatment of bladder cancer without muscle invasion
Prognostic markers and risk classification
The following information needs to be fully documented and used in the prognostic treatment discussion for non-muscle-invasive bladder cancer, involving the multidisciplinary team and the patient: history of recurrence; size and number of cancers; histological type, stage and involvement of the urethral epithelium, intrinsic muscular layer and carcinoma in situ; risk classification; and risk factors for recurrence and progression using risk prediction tools.
High-risk non-muscle-invasive bladder cancer
Patients are offered the option of intravesical BCG or radical cystectomy. Depending on the choice, patients, nursing specialists and urologists discuss: tumour type, staging classification, presence of carcinoma in situ and pathological variants, prostatic urethral and bladder neck status, number of tumours; risk of progression to muscle, risk of metastasis and death; staging
risk of understaging; benefits and risks of second treatment; factors affecting clinical outcome; impact on quality of life, self-morphological imaging, sexual function, urinary function
(4) Post-treatment follow-up for non-muscle invasive bladder cancer
Low-risk non-muscle-invasive bladder cancer without recurrence within 12 months may not be followed up; intermediate-risk non-muscle-invasive bladder cancer with cystoscopy at 3, 9 and 18 months and annually thereafter.
(5) Treatment of muscle-invasive bladder cancer
For newly diagnosed muscle-invasive uroepithelial bladder cancer treated with neoadjuvant cisplatin-containing combination chemotherapy followed by radical cystectomy or radical radiotherapy, patients need to discuss with their urologist: the relationship between treatment and prognosis; the limited evidence that surgery or radiotherapy combined with sensitising agents is the most effective treatment; the benefits and risks of radical treatment, including effects on sexual and bowel function, and the risk of death as a result of treatment.
1. Recommendations Determined on the basis of best evidence.
1.1 Obtain information and provide support for patients with bladder cancer
1.1.1 Always follow relevant NICE guidelines in communication and treatment.
1.1.2 Patients are offered support from a clinical nurse specialist and are informed of the details of their contact with the nurse specialist.
1.1.3 Ensure that the clinical nurse specialist is the main conduit for patient information and treatment needs; nursing staff need to be trained and experienced in bladder cancer care.
1.1.4 To fully assess and support information about patients with bladder cancer at the point of diagnosis, at the completion of the first treatment, at the time of disease recurrence or progression, at the time of change in treatment and when palliative or end-of-life care needs to be discussed.
1.1.5 Assess the patient thoroughly and know which symptoms, studies and treatments can affect the genitourinary organs and lead to feelings of frustration and distress. The following need to be discussed with the patient: tumour type, staging grading and prognosis; treatment and follow-up plans; possible complications of invasive treatment, including urinary retention, urinary tract infection, pain, bleeding or the need for catheters.
The impact of treatment on sexual health and self-image, including how to find information on relevant support; diet and lifestyle, including physical activity; smoking cessation; how to find information on bladder cancer through DVDs, websites and various written resources; how to find support groups and monitoring procedures; how to find information on how to return to work after cancer treatment; how to find information on financial support (e.g. free prescriptions and compensation schemes).
1.1.6 Provide support to stop smoking.
1.1.7 Provide opportunities for patients or relevant people to have discussions at any stage of treatment, including health workers such as psychologists, or patients with bladder cancer who have experienced the same treatment.
1.1.8 Ensure that ongoing treatment is closely linked to future supportive treatment in the community.
1.1.9 Conduct an annual survey of bladder cancer patient satisfaction and adjust procedures based on the results.
1.2 Diagnosis and staging of bladder cancer
Diagnosis
1.2.1 Do not use urinary biochemical markers instead of cystoscopy for suspected bladder cancer or for post-treatment follow-up, except for clinical studies.
1.2.2 CT or MRI staging should be performed prior to TURBT when cystoscopy suspects bladder cancer invading the muscularis.
1.2.3 Perform white light TUBRT and one of the following tests in patients with suspected bladder cancer: photodynamic diagnosis, narrow spectrum presentation, cytology or urinary biochemical markers (e.g. UroVysion using FISH, ImmunoCyt, or nuclear matrix protein 22 assay [NMP22]). These should be performed or supervised by a TURBT experienced urologist.
1.2.4 Obtain a myeloablative specimen for TURBT.
1.2.5 Do not randomise normal-appearing urethral epithelial biopsies during TURBT unless there is a clinical indication.
1.2.6 Record the size and number of tumours at the time of TURBT.
1.2.7 Give a single dose of intravesical mitomycin to patients with suspected bladder cancer at the same time as the initial TURBT.
Staging
1.2.8 Re-TUBRT within 6 weeks if the first specimen does not include a myelomeningocele specimen.
1.2.9 CT or MRI staging is required to assess radical treatment for bladder cancer with muscle invasion or high-risk non-muscle invasive bladder cancer.
1.2.10 Consider CT urography to detect the presence of upper urethral invasion in newly diagnosed or recurrent high-risk non-muscle-invasive or muscle-invasive bladder cancer.
1.2.11 Consider chest CT for muscle-invasive bladder cancer with chest invasion.
1.2.12 Consider FDG PET-CT for high-risk non-muscle-invasive or muscle-invasive bladder cancer if CT or MRI findings remain inconclusive prior to radical treatment or if there is a high risk of metastatic disease (e.g. T3b).
1.3 Treating non-muscle-invasive bladder cancer
Risk classification
There is no universally accepted risk classification and to facilitate treatment recommendations, the guideline panel reached consensus on the classification in the table below, which is based on systematic reviews and clinical opinion.
Risk stratification for non-muscle invasive bladder cancer.
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Prognostic markers and risk stratification
1.3.1 There is a need to ensure that the following information on non-muscle invasive bladder cancer is fully documented and used in the prognostic treatment discussion, involving the multidisciplinary collaborative group and the patient: history of recurrence; size and number of cancers; histological type, stage and involvement of the urethral epithelium, intrinsic muscular layer and carcinoma in situ; risk classification; and risk factors predictive of recurrence and progression using risk prediction tools.
Low-risk non-muscle-invasive bladder cancer
1.3.2 See 1.2.3C1.2.8 for treatment recommendations.
Intermediate-risk non-muscle-invasive bladder cancer
1.3.3 One course of treatment: at least 6 intravesical mitomycin treatments.
1.3.4 Recurrence after one course of intravesical mitomycin therapy and referral to a urological specialist with a multidisciplinary team.
High risk non-muscle invasive bladder cancer
1.3.5 Give a second TURBT as soon as possible and no later than 6 weeks after the initial TURBT indicates high-risk non-muscle invasive bladder cancer.
1.3.6 Offer the patient the choice of intravesical infusion of BCG or radical cystectomy. Depending on the choice, the patient, nursing specialist and urologist discuss: tumour type, staging classification, presence of carcinoma in situ and pathological variants, prostatic urethra and bladder neck status, number of tumours; risk of progression to the muscularis, risk of metastasis and mortality risk of under-staging; benefits and risks of the two treatments; factors affecting clinical outcome; impact on quality of life, self-image, sexual function, urinary function
Intravesical BCG
1.3.7 Administer induction and maintenance intravesical BCG therapy.
1.3.8 If BCG induction therapy fails (intolerance or persistence of bladder cancer or recurrence after BCG therapy), refer to a specialist urological clinic with a multidisciplinary team.
1.3.9 In cases of failed BCG induction, the multidisciplinary team should assess the appropriateness of radical cystectomy and, if inappropriate or if the patient does not consent or if the recurrent bladder cancer is low to intermediate risk, further intravesical treatment should be undertaken.
Radical cystectomy
1.3.10 Refer to recommendation 1.5.4C1.5.7.
Recurrent non-muscle invasive bladder cancer
1.3.11 Electrocautery may be considered without biopsy for recurrent non-muscle-invasive bladder cancer if the following conditions are met: no previous history of intermediate to high-risk bladder cancer; a disease-free interval of at least 6 months; a single papillary recurrence; and a tumour diameter of less than 3 mm.
Management of treatment side effects
1.3.12 Prevention of BCG-related bladder toxicity is not required, unless it is part of a clinical trial.
1.3.13 If symptoms of bladder toxicity develop after BCG that cannot be controlled with antitussive medication or non-opiate analgesics and cystoscopy has excluded other causes, consult a multi-collaborative group specialist.
1.4 Post-treatment follow-up for non-muscle invasive bladder cancer
1.4.1 If a patient presents with haematuria or other urinary tract symptoms and has a history of non-muscle invasive bladder cancer, refer the patient to a urologist as soon as possible.
1.4.2 Refer to recommendation 1.2.1 for post-treatment follow-up of bladder cancer using urinary biochemical markers.
Low-risk non-muscle invasive bladder cancer
1.4.3 Cystoscopic follow-up should be performed after diagnosis, at 3 and 12 months respectively.
1.4.4 Cystoscopic follow-up is used after treatment and no urinary biochemical markers or cytological follow-up is used.
1.4.5 Low-risk non-muscle-invasive bladder cancer without recurrence at 12 months can be discontinued…
1.4.6 No routine urine cytology or extended cystoscopy follow-up after 12 months.
Intermediate-risk non-muscle-invasive bladder cancer
1.4.7 Patients with intermediate-risk non-muscle-invasive bladder cancer should have cystoscopy at 3, 9 and 18 months and annually thereafter.
1.4.8 No further treatment after 5 years of continuous disease-free follow-up.
High-risk non-muscle-invasive bladder cancer
1.4.9 Follow up with cystoscopy: every 3 months for the first 2 years; every 6 months for years 3 and 4; and annually thereafter.
1.4.10 Refer to recommendations 1.6.1 and 1.6.2 for those who have undergone radical cystectomy.
1.5 Treatment of muscle-invasive bladder cancer
1.5.1 Ensure that the expert collaborative group reviews each case, including adenocarcinoma, squamous carcinoma and neuroendocrine carcinoma, with the review including histopathology, imaging and discussion of treatment options.
Neoadjuvant chemotherapy for newly diagnosed muscle-invasive uroepithelial bladder cancer
1.5.2 Give a combination regimen containing cisplatin for neoadjuvant chemotherapy followed by radical cystectomy or radical radiotherapy, ensuring that the patient has the opportunity to discuss the risks and benefits with a urologist.
Radical treatment of muscle-invasive uroepithelial bladder cancer
1.5.3 Radical cystectomy or radiotherapy combined with sensitiser treatment can be offered to patients suitable for radical treatment. It is important to ensure that the choice of treatment is one that has been fully discussed by the patient, urologist and caregiver: the relationship between treatment and prognosis; the limited evidence that surgery or radiotherapy combined with sensitiser is the most effective treatment; the benefits and risks of radical treatment, including effects on sexual and bowel function, and the risk of death as a result of treatment.
Radical cystectomy
1.5.4 Urethrostomy for those opting for radical cystectomy or urethral diversion if not contraindicated; contraindications include cognitive impairment, reduced renal function or significant bowel disease.
1.5.5 The multidisciplinary collaborative team (including bladder cancer surgeons, fistula care specialists and clinical nurses) should discuss with the patient whether to perform a urostomy or urethral diversion and provide the patient with the opportunity to talk to someone who has had this experience.
1.5.6 Before and after radical cystectomy, patients or their families should be given the opportunity to discuss with a fistula care specialist if necessary.
Adjuvant chemotherapy for muscle-invasive or lymph node-positive uroepithelial bladder cancer after radical cystectomy
1.5.7 If neoadjuvant chemotherapy is not appropriate (no muscle invasion on pre-bladder resection biopsy), then adjuvant cisplatin-containing chemotherapy should be considered postoperatively. Ensure that the patient has the opportunity to discuss the risks and benefits with the oncologist.
Radical radiotherapy
1.5.8 For radical radiotherapy (e.g. 64 Gy, 32 doses for 6.5 weeks or 55 Gy, 20 doses for 4 weeks), use a radiotherapy sensitiser (e.g. mitomycin in combination with 5-FU or carboglobulin in combination with nicotine).
Managing treatment side effects
1.5.9 If symptoms of bladder toxicity after radiotherapy are not controlled with anti-spasmodic drugs or non-opiate analgesics, and cystoscopy has excluded other causes, consult a multi-collaborative group specialist.
1.6 Follow-up after treatment for muscle invasive bladder cancer
1.6.1 Follow up after radical cystectomy or radiotherapy.
1.6.2 Follow-up protocols may include: imaging and GFR assessment, monitoring for hydronephrosis, stones and cancer at least annually; abdominal, pelvic and chest CT to monitor for local and distant recurrence at 6, 12 and 24 months post-operatively; monitoring for metabolic acidosis, B12 and folic acid deficiency at least annually; urethral flush cytology and / urethroscopy in men with a functionally abnormal urethra for urethral recurrence, once a year for 5 years.
1.6.3 Follow-up after radical radiotherapy should include all of the following: hard cystoscopy 3 months after radiotherapy; then hard or soft cystoscopy every 3 months for the first 2 years; every 6 months for years 3 and 4; and annually thereafter; imaging of the upper urinary tract, annually for 5 years; and CT of the abdomen, pelvis and chest to monitor local and distant recurrences at 6, 12 and 24 months after radiotherapy. 1.6.4 Bladder
1.6.4 See recommendation 1.2.1 for the use of urinary biochemical markers as follow-up after treatment for bladder cancer.
1.7 Treatment of locally progressive or metastatic muscle invasive bladder cancer
First-line chemotherapy
1.7.1 Discuss the role of first-line chemotherapy with the patient, including: the prognosis of the cancer, the advantages and disadvantages of treatment options, including best supportive care.
1.7.2 Offer cisplatin-containing combination chemotherapy (e.g. cisplatin + gemcitabine, or high-dose methotrexate, vincristine, adriamycin, cisplatin [MVAC] with an ECOG score of 0 or 1), provided the patient has normal renal function.
1.7.3 If a cisplatin-containing regimen is not appropriate, e.g. if the ECOG score is unsatisfactory, or if renal GFR is <60 ml/min/1.73 m2 , or if complications exist, a carboplatin-containing regimen may be given in combination with chemotherapy. Assess and discuss risks and benefits.
1.7.4 Perform routine clinical and imaging investigations, treatment of disease-related symptoms and treatment-related toxicity in patients undergoing first-line chemotherapy and discontinue first-line therapy if toxicity is excessive or disease progresses.
Second-line chemotherapy
1.7.5 Discuss second-line chemotherapy with the patient, including the following: prognosis of the cancer, advantages and disadvantages of treatment options, including best supportive care.
1.7.6 If renal function is adequate and ECOG score 0 or 1, consider second-line chemotherapy with gemcitabine in combination with cisplatin, or high-dose MVAC.
1.7.7 If cisplatin is unsuitable or unacceptable to the patient, choose carboplatin in combination with paclitaxel or gemcitabine in combination with paclitaxel.
1.7.8 If vincristine is used as second-line chemotherapy, see NICE technology appraisal guidance.
1.7.9 Perform routine clinical and imaging investigations, treatment of disease-related symptoms and treatment-related toxicity in patients undergoing second-line chemotherapy and discontinue second-line therapy if toxicity is excessive or disease progression occurs.
Treat symptoms of locally progressive or metastatic bladder cancer
Bladder symptoms
1.7.10 Palliative split radiotherapy may be given to patients with carnal haematuria, dyspareunia, dysuria or nocturia arising from bladder cancer and who are not candidates for curative treatment.
Low back pain and symptoms of renal insufficiency
1.7.11 For patients with ureteral obstruction discuss treatment options, including: prognosis of the cancer, advantages and disadvantages of treatment options, including best supportive care.
1.7.12 Percutaneous nephrostomy or stenting may be considered for patients with ureteral obstruction prior to further treatment and where the patient needs pain relief, treatment of acute kidney injury or improvement in renal function.
1.7.13 If percutaneous nephrostomy or stenting is not available or is unsuccessful, further treatment needs to be discussed with the multidisciplinary team.
Refractory haemorrhage
1.7.14 Assess the cause of the bleeding.
1.7.15 Consider split radiotherapy or embolisation if due to bladder cancer.
1.7.16 If radiotherapy or embolisation is not appropriate, discuss further treatment with the multidisciplinary team.
Pelvic pain
1.7.17 Assess the cause of the pain.
1.7.18 In addition to best supportive care, consider the following treatments if the pain is due to bladder cancer: split radiotherapy, nerve block, palliative chemotherapy if no previous pelvic radiotherapy has been administered.
1.8 Palliative treatment of incurable bladder cancer
1.8.1 Patients should be explained that their disease is incurable and referred to a multidisciplinary team.
1.8.2 The multidisciplinary team should be informed within 24 hours of informing the patient that he/she has incurable bladder cancer.
1.8.3 The prognosis and treatment options should be discussed with the patient with incurable bladder cancer.
1.8.4 Discuss palliative care and refer to a specialist palliative care team if necessary and if the patient agrees.
1.8.5 Provide the patient with options and pathways for the treatment of all symptoms.
The following needs to be noted.
[1] At the time of publication of this guideline there was no UK market access for mitomycin in combination with fluorouracil and prescribers are responsible for decisions made and patients need to give informed consent in accordance with the guideline.
[2] Carboglobulin in combination with nicotine, carboplatin in combination with gemcitabine and gemcitabine in combination with paclitaxel, although commonly used in the UK, do not have UK market access and prescribers are responsible for their decisions and patients need to give informed consent in accordance with the guideline.
2. Study recommendations
The Guideline Development Group made the following recommendations for the study to improve NICE guidelines and patient care.
2.1 Patient satisfaction
Bladder cancer patients were the least satisfied compared to other cancers. This group had the lowest caregiver quotas; prolonged invasive procedures due to research, treatment and follow-up needs may also have contributed to poor satisfaction; bladder cancer patients nearing the end of life are often elderly and frail, with little opportunity for palliative support treatment, sometimes confined to general wards where pain and haematuria are not well managed. Exploring the causes of the problem requires that bladder cancer be studied separately.
2.2 BCG or cystectomy for patients with high-risk non-muscle-invasive bladder cancer
Treatment options for patients with high-risk non-muscle-invasive bladder cancer include cystoscopic monitoring, BCG immunotherapy or radical surgery. To date, there is no direct comparison between these treatments. While bladder preservation avoids major surgery, the risk of cancer progression is greater and the benefits of bladder preservation are offset by the ongoing concerns about whether the cancer is progressing and the comorbidities of treatment.
Cystectomy may improve survival, but carries short-term risks and is life-changing. For those patients who do not progress it is overtreatment. It is inconclusive whether radical cystectomy or intravesical BCG treatment is better or worse in terms of quality of life and cancer-specific outcomes.
2.3 Follow-up of high-risk non-muscle-invasive bladder cancer
The two follow-up schedules for patients with high-risk non-muscle-invasive bladder cancer are as follows: cystoscopy at 3, 6, 12, 18, 24, 36 and 48 months and then annually, supplemented by urinalysis; and cystoscopy at 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42 and 48 months and then annually.
Cystoscopy is the standard follow-up procedure for patients at high risk of non-muscle invasive bladder cancer, but regular cystoscopy produces anxiety, discomfort and significantly increased costs to the NHS. Urinalysis can detect high-grade recurrence and a combination of 1 or more urinalysis methods can reduce the frequency of screening, improve patient acceptance and reduce costs without increasing the risk of disease progression.
There is no evidence to support how the frequency of follow-up is most appropriate and whether the currently recommended frequency of microscopy can be safely replaced by urine testing.
2.4 Biochemical markers to determine treatment choice
Response to surgery or radiotherapy is difficult to predict, cure rates and side effects vary from patient to patient, and the use of biochemical markers to predict treatment outcome is not well established. Modern treatment decisions rely heavily on patient factors and patient and physician preferences, and the discovery of biochemical markers that predict response to surgery or radiotherapy can be very helpful to patients and physicians in deciding treatment choice and is a key step in individualising treatment.
2.5 Follow-up after radical treatment for bladder cancer confined to muscle invasion of the bladder
Patients are recommended by the treatment team for scheduled follow-up at defined intervals after radical treatment, but it is not possible to determine whether there is a real clinical benefit at significant cost compared with return visits by symptoms. The current evidence on follow-up is limited to cystectomy, with no evidence focusing on follow-up after radiotherapy, and the evidence on imaging follow-up is also limited to those with outdated imaging techniques. Further research is needed on overall survival, health-related quality of life, use of resources and costs after radical treatment with return visits by symptom and follow-up by plan.