1 OVERVIEW
Bladder cancer (BC) ranks as the ninth most common malignancy globally, being the seventh most prevalent in men and tenth in women. Its mortality rates are significantly higher in men (3.2 per 100 000) than in women (0.9 per 100 000). This cancer poses a serious public health challenge, highlighting the importance of standardized diagnosis and treatment, especially in China.
BC treatment varies depending on the cancer stage, pathology, and the patient's health. It is categorized into non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC). For NMIBC, the primary treatment is transurethral resection of bladder tumor (TURBt), followed by tailored intravesical chemotherapy based on recurrence risk. In MIBC, a more aggressive, surgery-centered approach is adopted, typically involving radical cystectomy, though partial cystectomy may be suitable in some cases. The necessity of adjuvant chemotherapy or radiotherapy is determined postsurgery. Metastatic BC primarily relies on systemic chemotherapy, supplemented by palliative surgery and radiotherapy for symptom management.
Succeeding the first part of the guideline[
1], this part of the guideline specifically dwells on NMIBC treatment, discussing risk stratification, operational highlights of TURBt, and guidelines for selecting appropriate intravesical instillation agents.
2 TREATMENT APPROACHES FOR BC
Treatment options for BC vary according to the cancer's stage and pathology, as well as the patient's health condition.
Basic treatment modalities for BC: The cornerstone treatment for NMIBC is TURBt. Following TURBt, intravesical chemotherapy regimen is tailored to the individual's risk of recurrence.
In cases of MIBC, squamous cell carcinoma, adenocarcinoma, and urachal cancer, a surgery-centered comprehensive treatment strategy is preferred. Radical cystectomy is often the treatment of choice, while partial cystectomy may be suitable for certain patients. Preoperative neoadjuvant chemotherapy is recommended for T2 ~ 4aN0M0 urothelial carcinoma. The need for postoperative adjuvant chemotherapy and/or radiotherapy is determined based on the results of surgical pathology. Systemic chemotherapy is the mainstay for treating metastatic BC, with palliative surgery and radiotherapy added for symptom relief.
3 TREATMENT STRATEGIES FOR NMIBC
3.1 Risk classification in NMIBC
NMIBC comprises malignant bladder tumors confined to the mucosa (Ta) and lamina propria (T1), with no muscular invasion. This category includes Ta, T1, and carcinoma in situ (Tis) stages, collectively accounting for approximately 75% of BC cases, within which Ta tumors account for 70%, T1 tumors 20%, and Tis 10%. While both Ta and T1 stages fall under NMIBC, they differ significantly in their biological characteristics. The T1, rich in blood vessels and lymphatics, makes T1 stage tumors more prone to spread.
Risk factors influencing the recurrence and progression of NMIBC include total tumor count, tumor size, stage, and grade, frequency of recurrence, existence of Tis, and so forth.
Risk factors for recurrence include having a high tumor count (≥8) and a frequency of recurrence greater than once per year. Risk factors for progression include the staging of the tumor (T1), the grade of the tumor (G3 or high-grade urothelial carcinoma), and the Tis. NMIBC is categorized into four distinct risk groups based on the prognosis and risk of recurrence (see Table 1).
3.2 Surgical treatment of NMIBC
The appropriate choice of surgical procedure, along with bladder instillation and follow-up plans, is guided by the NMIBC risk groups (see Table 2).
3.2.1 TURBt
TURBt is not only the standard treatment modality for NMIBC but also plays a crucial role during the diagnostic workup. This technique is favored as it incurs minimal risk of tissue trauma and bleeding, and it facilitates a swift recovery postoperation. TURBt is the first-line treatment for NMIBC patients.
The primary objective of TURBt is the complete removal of the tumors until the healthy detrusor muscle of the bladder wall is visible. To ensure precision in staging and grading, it is advisable to separately send the basal tissue layer, obtained during tumor resection, for pathological examination. An accurate assessment of the tumor's grade and pathological stage aids in formulating an appropriate and effective subsequent treatment plan.
Methods employed for complete tumor resection during TURBt include segmented resection (involves removal of the tumor, the basal layer of the bladder wall, and the edge of the resection area) or en-bloc resection (entails removing the entire tumor in one piece, using tools such as monopolar or bipolar electrotomy, thulium laser, or holmium laser fibers).
For smaller tumors (<1 cm), the tumor and the detrusor muscle at its base can be removed together and sent for pathological examination. Larger tumors are resected in segments: The procedure involves first dissecting the protruding part of the tumor, followed by the removal of its base, continuing until the normal detrusor muscle of the bladder wall is exposed. It is crucial for determining the pathological staging that the base of the resected specimen includes tissues from the muscular layer. Minimizing cauterization during TURBt is recommended to reduce potential damage to the specimen.
For small recurrent Ta/G1 tumors identified during outpatient cystoscopy, fulguration can be an effective treatment method.
In patients with multiple lesions or Tis, narrow-band imaging (NBI)-guided TURBt can be employed. This advanced technique enhances tumor detection and reduces the likelihood of missed diagnoses. The impact of NBI-guided TURBt on overall treatment efficacy continues to be a subject of ongoing research and validation.
3.2.2 Re-TURBt in NMIBC
Postoperative recurrence of NMIBC is often attributed to residual tumors remaining after the first TURBt. The incidence of residual tumors varies widely (4%–78%), influenced by factors such as the tumor's stage, size, number, and the surgeon's skill level. Specifically, the residual disease rate is 22% for focal lesions and 45% for multifocal disease. For lesions smaller than 3 cm, the rate is 19%, and it increases to 42% for lesions 3 cm or larger. Intermediate- and high-grade T1 tumors have a residual disease rate of 33%–55%, and for TaG3 tumors, this rate is 41.4%.
Variations in surgical techniques and issues with the quality of specimens can lead to significant variations in pathological staging. Studies indicate that 1.3%–25% of patients initially diagnosed with T1 stage disease are later found to have MIBC after re-TURBt. This is particularly true when the first TURBt specimen lacks detrusor muscle component, with 45% of these cases later confirmed as MIBC. Re-TURBt can correct the pathological diagnosis in 9%–49% of patients.
Impact of re-TURBt on treatment outcomes: A multicenter retrospective study involving 2451 cases of T1G3/HG tumors treated with Bacille Calmette–Guérin (BCG) intravesical instillation, 935 of which underwent re-TURBt, demonstrated that re-TURBt can significantly improve recurrence-free survival, progression-free survival, and overall survival rates, especially in patients whose initial TURBt specimens did not contain detrusor muscle. Specifically, it reduced the postoperative recurrence rate of T1 tumors from 63.24% to 25.68% and the tumor progression rate from 11.76% to 4.05%. Over a 10-year follow-up period, the disease-free survival rate for patients with high-grade T1 tumors was 69.7% for those who underwent re-TURBt, compared to 49.6% for those who only underwent a single TURBt.
Re-TURBt can uncover residual lesions for more accurate pathological staging, and significantly improve treatment outcomes, recurrence-free survival, and overall prognosis.
(1) Indications for re-TURBt include: ① The first TURBt was inadequate; ② absence of detrusor muscle in the specimen, except for cases involving TaG1/low-grade tumors and simple Tis; ③ presence of T1 tumors; ④ presence of G3 (high-grade) tumors, excluding cases of Tis.
(2) Timing of re-TURBt: If the interval between the initial TURBt and re-TURBt is too long then the efficacy of subsequent intravesical infusion chemotherapy may be affected. If this interval is too short, mucosal swelling and inflammation can hinder the identification of residual tumors.
Currently, the recommended timeframe for re-TURBt is approximately 2–6 weeks following the first operation. The resection should revisit the original tumor site and extend to the depth of the detrusor muscle.
(3) Key surgical considerations: The initial step involves resecting the base of the original tumor, including the surrounding inflamed edematous mucosa, followed by addressing any new suspected tumor sites. The resection should reach the deep detrusor muscle layer. It is recommended that biopsies of the base of the lesion should be taken with biopsy forceps or electric cutting loops, and random biopsies should be performed if necessary.
(4) Intravesical instillation post-re-TURBt: Immediate intravesical instillation, within 24 hours after re-TURBt, is recommended. However, it is not recommended for patients who have experienced intraoperative bladder perforation or severe gross hematuria. For high-risk NMIBC cases where no residual tumor is found post-re-TURBt, instillation of BCG or chemotherapeutic drugs is recommended. In cases where re-TURBt confirms the presence of a residual tumor, BCG intravesical instillation or cystectomy is suggested. If re-TURBt rebuts the initial pathological diagnosis and the diagnosis is revised as MIBC, then radical cystectomy is recommended.
3.2.3 Transurethral laser resection of bladder tumors
En-bloc TURBts can facilitate the collection of larger detrusor muscle specimens, which are essential for accurate histopathological staging. Laser resection is known for its effective vaporization capabilities, precise tissue cutting, and reduced likelihood of intraoperative bleeding. Additionally, it minimizes the risk of triggering the obturator nerve reflex. These features make laser technology particularly suitable for en-bloc resection of NMIBC.
In clinical settings, various types of laser fibers are employed, including holmium laser fibers, green laser fibers, thulium laser fibers, and 1470 semiconductor laser fibers. The short-term efficacy of transurethral laser resection of bladder tumors has been found to be comparable to that of traditional TURBt, but ongoing studies are needed to fully establish its long-term benefits.
3.2.4 Partial cystectomy
While TURBt is effective for the vast majority of NMIBC cases, partial cystectomy is reserved for specific scenarios. It is particularly considered, to reduce the risk of bladder perforation caused by fulguration, for solitary tumors that have adequate resection margins, or for tumors located within a diverticulum where Tis is not detected upon random biopsy. Pelvic lymph node dissection to be performed with partial cystectomy is recommended, covering at least the common iliac, internal iliac, external iliac, and obturator lymph nodes. Postoperative intravesical instillation of immunotherapeutic drugs or systemic adjuvant chemotherapy is recommended following a partial cystectomy. These postsurgical treatments are geared toward reducing the risk of cancer recurrence and addressing any residual microscopic disease.
3.2.5 Radical cystectomy
For some high-risk NMIBC or the highest risk subgroup of NMIBC, radical cystectomy is indicated when the following conditions are present: Those with multiple and/or recurrent high-grade tumors, high-grade T1 tumors, high-grade tumors accompanied by concurrent Tis, lymphovascular invasion, micropapillary characteristics, or in cases where BCG intravesical therapy has failed. For patients who are either unwilling or unable to undergo radical cystectomy, alternative treatment options include chemoradiotherapy or a combination of TURBt and BCG intravesical instillation. It is crucial that patients are thoroughly informed about the advantages and disadvantages of different treatment options, and the decision must be made through discussion with the patient.
3.3 Post-TURBt intravesical instillation therapy in NMIBC
NMIBC patients experience a notable rate of post-TURBt recurrence, ranging from 24% to 84% within 5 years. This recurrence is often attributed to factors such as incomplete resection of the primary tumor, tumor seeding, or the emergence of new focal lesions. In some instances, these recurrences may progress to MIBC. Therefore, it is strongly advised that all NMIBC patients receive postoperative adjuvant intravesical instillation, including intravesical chemotherapy and intravesical immunotherapy (Tables 3 and 4).
3.3.1 Intravesical chemotherapy
3.3.1.1 Timing of intravesical instillation
① Immediate postoperative intravesical chemotherapy: This is effective in eradicating migrating tumor cells that may have been disturbed during the surgical procedure, as well as targeting any postfulguration residual tumor cells, thus significantly reducing the likelihood of tumor recurrence.
Studies underscore the efficacy of this treatment strategy. In a study involving 2844 NMIBC cases, those who had undergone mitomycin C instillation immediately after TURBt experienced a recurrence rate of 27%, which is notably lower than the 36% recurrence observed in the control group. Furthermore, a phase III clinical study highlighted that immediate postoperative instillation of gemcitabine reduced the recurrence rate by 34% compared with the control group figure.
A recent meta-analysis involving 2278 patients with NMIBC has revealed that administering intravesical chemotherapy immediately after TURBt leads to a significant reduction in the 5-year recurrence rate by 35% (hazard ratio [HR] 0.65, p < 0.001), but it did not appear to lower the risk of tumor progression and mortality.
In light of these findings, it is advised that all NMIBC patients receive intravesical chemotherapy promptly following surgery, and the intravesical instillation should be completed within 24 h after the operation, ideally within the first 6 h. It is important to note that immediate infusion of chemotherapy is not advisable in cases where intraoperative bladder perforation or severe postoperative hematuria has occurred.
② Early-postoperative intravesical chemotherapy and maintenance intravesical chemotherapy: Following immediate postoperative instillation, patients diagnosed with intermediate- and high-risk NMIBC are advised to undergo a maintenance phase of intravesical instillation. This involves administering chemotherapeutic agents or BCG to effectively reduce the likelihood of tumor recurrence. According to current guidelines, the duration of intravesical chemotherapy should not exceed one year.
3.3.1.2 Intravesical instillation regimen
This includes, in the early induction phase, once a week for 4–8 weeks following surgery; in the subsequent maintenance phase, once a month for 6–12 months.
① In cases of low-risk NMIBC, where the tumor recurrence rate postimmediate instillation is notably low, continuing with maintenance bladder instillation is not generally recommended.
② Patients with intermediate-risk NMIBC are usually recommended to continue intravesical chemotherapy once a week for 8 weeks, followed by monthly instillations for 10 months after the immediate postoperative instillation. BCG instillation is also considered a viable option for these patients.
③ For those with high-risk NMIBC, postoperative intravesical instillation of BCG is advised to prevent both recurrence and progression of the disease. In situations where recurrent lesions are resistant to BCG, the use of chemotherapeutic drugs for maintenance instillation is an alternative approach.
At present, there is no substantial evidence indicating significant differences in efficacy between various chemotherapeutic drugs used in maintenance regimens. However, it is generally advised not to extend intravesical chemotherapy beyond one year.
3.3.1.3 Selection of intravesical chemotherapeutic agents
Commonly used intravesical chemotherapeutic agents include: mitomycin (20–60 mg), gemcitabine (1000 mg), pirarubicin (30–50 mg), epirubicin (50–80 mg), doxorubicin (30–50 mg), and hydroxycamptothecin (10–20 mg).
These chemotherapy drugs should be administered into the bladder via a Foley catheter and typically retained for a duration of 0.5–2 h. The effectiveness of intravesical chemotherapy is influenced by factors such as urine pH, the dosage and concentration of the drugs, and the duration of drug action. It is recommended to restrict water intake for 6 h before instillation to minimize urine output and prevent dilution of the chemotherapeutic agents within the bladder.
The primary side effect of intravesical chemotherapy is chemical cystitis, which manifests as bladder irritation and gross hematuria. The severity of this condition is related to the dosage and frequency of the chemotherapy instillations. While mild cases often find relief through adequate hydration between treatments, severe cases of bladder irritation may necessitate a delay or cessation of the instillation. Fortunately, most side effects typically resolve once the chemotherapy instillation is discontinued.
3.3.2 Intravesical immunotherapy
Intravesical immunotherapy predominantly utilizes BCG, complemented by other biological agents such as Pseudomonas aeruginosa, Streptococcus pyogenes, and Nocardia rubrum preparations.
BCG instillation is the first-line adjuvant therapy for high-risk NMIBC following TURBt.
The precise mechanism through which BCG operates remains incompletely understood. However, it is known that intravesical instillation of BCG can trigger local immune responses. These responses may directly target and eliminate tumor cells or indirectly produce antitumor effects through nonspecific immune responses, primarily mediated by Th1 cells. BCG is effective in preventing tumor recurrence and slowing disease progression. However, its impact on overall survival and specific tumor survival in bladder cancer patients has yet to be conclusively determined.
3.3.2.1 Indications for BCG intravesical instillation
BCG intravesical instillation is suitable for intermediate- and high-risk NMIBC, and Tis. It is, however, not recommended for low-risk NMIBC. Compared to TURBt alone, combining TURBt with postoperative BCG instillation significantly reduces the risk of NMIBC recurrence and progression in intermediate- and high-risk cases. Consequently, BCG intravesical immunotherapy is particularly advocated for high-risk NMIBC.
The 5-year postoperative recurrence rate for intermediate-risk NMIBC ranges from 42% to 65%, with a progression risk of 5% to 8%. In such cases, intravesical chemotherapy is generally recommended.
A multicenter randomized controlled trial (RCT) has confirmed that for patients with intermediate-risk NMIBC, BCG instillation is more effective than intravesical chemotherapy in preventing tumor recurrence, and the efficacy of intravesical immunotherapy is relatively durable, effectively delaying tumor progression. Based on the result from this RCT, some patients can opt for a yearlong BCG instillation treatment regimen.
In 2015, the European Organization for Research and Treatment of Cancer analyzed two phase III clinical studies focusing on BCG intravesical instillation. These studies, which involved BCG treatment for 1–3 years with an average follow-up period of 7.4 years, revealed that the likelihood of T1G3 NMIBC cases advancing to MIBC within 5 years was 19.3%. Notably, 45% of the subjects in these studies were classified as high-risk NMIBC cases. Compared to those treated with mitomycin instillation, high-risk patients who received BCG instillation had a 32% lower risk of recurrence and a 27% lower rate of tumor progression. These results suggest that using BCG as a maintenance intravesical immunotherapeutic agent may lead to even more favorable outcomes.
Furthermore, for patients with bladder urothelial Tis, BCG intravesical instillation showed a notably high complete response rate ranging between 72% and 93%. This rate is significantly superior to the response rate of intravesical chemotherapy, which stands at 48%. BCG instillation also markedly reduces the rates of tumor recurrence and progression in these patients. Thus, postoperative BCG instillation is highly recommended for patients diagnosed with Tis.
3.3.2.2 BCG instillation is contraindicated in several scenarios to ensure patient safety
This applies within 2 weeks of TURBt; patients with active tuberculosis or severe hematuria; situations involving posttrauma Foley catheterization; presence of symptomatic urinary tract infection; immunodeficient patients or those in an immunosuppressive state (including patients with AIDS, those on immunosuppressants, or undergoing radiotherapy); patients with confirmed BCG allergies; and so forth.
3.3.2.3 BCG intravesical instillation regimen and dosage
The optimal regimen and course of BCG intravesical instillation are currently not definitively established.
① Optimal timepoint for instillation: If there are visible wounds on the bladder wall or if the patient presents with gross hematuria, immediate instillation can lead to serious side effects and increase the risk of disseminating tuberculosis. Immediate postoperative instillation is strictly prohibited, and intravesical BCG instillation is typically started at least 2–4 weeks after surgery.
② Instillation regimen and dosage: The initial phase of BCG instillation, known as the induction phase, involves weekly treatments for the first six sessions. Various options exist for the maintenance phase, but no specific regimen has been conclusively proven to be superior to others.
Recommended protocol for BCG produced by Chinese pharmaceutical companies: Following the six rounds of instillation at the induction phase, an intensive treatment consisting of instillations every 2 weeks is performed for a total of three rounds. This phase aims to maintain an adequate level of immune reactivity. Thereafter, the maintenance phase involves once-a-month instillations for a total of 10 rounds. In total, the protocol prescribes 19 rounds of BCG instillation over the course of 1 year.
An RCT study demonstrated that the 19-round BCG instillation regimen yields a higher 1-year recurrence-free survival rate compared to a 15-round regimen.
Typically, 60–120mg of BCG is dissolved in 50–60 mL of normal saline for each instillation, and the solution is retained in the bladder for 2h per treatment. The recommended full dosage of domestically produced BCG is 120 mg. After the initial six rounds of weekly induction therapy, the maintenance phase should continue for 1–3 years, with a minimum of 1 year. Maintenance instillations are scheduled at 3, 6, 12, 18, 24, and 36 months, with each instillation period consisting of once a week for a total of three times per month (15 times in the first year), to sustain and enhance the efficacy of the BCG treatment. Full-dose BCG instillation has been found to be more effective than a third-dose BCG instillation.
For patients with high-risk bladder cancer, a 3-year continuation of BCG maintenance therapy is recommended, which has been found effective in preventing recurrence. For intermediate-risk patients, the recommended duration of BCG maintenance therapy is 1 year.
3.3.2.4 Adverse reactions to BCG intravesical instillation
The overall incidence of adverse reactions to BCG intravesical instillation is approximately 71.8%, most of which are localized, with about 60.1% classified as grade 1–2 (mild to moderate) reactions. The common adverse reactions include bladder irritation symptoms, hematuria and influenza-like syndrome, and fever. While rare, serious adverse reactions can include tuberculosis, sepsis, granulomatous prostatitis, epididymo-orchitis (inflammation of the epididymis and testicle), bladder contracture, tuberculous pneumonia, joint pain and/or arthritis, allergic reactions, and so forth. They can be alleviated by discontinuing the BCG instillation and administering appropriate symptomatic treatment.
3.3.2.5 Types of failed BCG intravesical instillation
① Refractory to BCG: This occurs when high-grade tumors are found within 6 months of completing an adequate course of intravesical immunotherapy. It also includes cases where the primary tumor progresses in grade and stage within 3 months following a round of BCG instillation.
② BCG recurrence: This type is characterized by the recurrence of high-grade tumors after an adequate course of BCG treatment and at least 6 months of being tumor-free. Specifically, this refers to recurrences occurring within 6–9 months after the last BCG instillation.
③ BCG-unresponsive: This genre encompasses both BCG-refractory and BCG-recurrence cases. In such situations, the recommended course of action is often radical cystectomy. For patients who are not suitable for surgery, a bladder-preserving comprehensive treatment regimen may be considered as an alternative.
Intermediate-risk NMIBC patients who encounter nonhigh-grade recurrence post-BCG intravesical immunotherapy may opt to either undergo another round of BCG instillations or receive radical cystectomy.
3.3.3 Pembrolizumab (immune checkpoint inhibitor)
A single-arm phase II clinical study (KEYNOTE-057) used pembrolizumab to treat 103 cases of NMIBC patients who did not respond to previous BCG therapy. The study specifically targeted high-risk NMIBC patients, including those with Tis, who were either not suitable or unwilling to undergo radical cystectomy. The 3-month complete remission rate was recorded at 38.8% (95% confidence interval [CI], 29.4–48.9). At the median follow-up time of 14.0 months, a consistent complete remission rate of 72.5% was observed. Among the 96 patients assessed for response, the complete response rate stood at 41% (95% CI, 31–51), with the median duration of response being 16.2 months. Importantly, 46% of the cases maintained complete responses for a minimum of 1 year. Treatment-related adverse events of grade three or higher were experienced by 12.6% of the patients. Immune-related adverse events constituted 18.4% of all adverse events reported.
3.3.4 Other intravesical treatments
3.3.4.1 Photodynamic therapy
Photodynamic therapy involves instilling photosensitizers (such as aminolevulinic acid and hexaminolevulinate) into the bladder, followed by irradiation of the entire bladder with a laser through a cystoscope. Tumor cells absorb the photosensitizer, which then produces singlet oxygen under laser irradiation, leading to necrosis of the tumor cells. Intravesical photodynamic therapy has shown potential in reducing the rates of tumor recurrence and progression. However, its effectiveness still requires further validation through multicenter clinical studies with larger sample sizes.
Indications for photodynamic therapy: Patients with Tis, those experiencing repeated recurrences, patients unable to tolerate surgery, and those who have not responded to BCG intravesical immunotherapy.
3.3.4.2 Intravesical hyperthermic chemotherapy with perfusion technique
This technique involves heating chemotherapeutic drugs using specialized equipment. The combination of heat energy and chemotherapy drugs aims to enhance the anti-tumor effect. A typical application of this technique is intravesical hyperthermic chemoperfusion with mitomycin (e.g., mitomycin C 20 mg + 50 mL of distilled water) at temperatures above 42°C for 1 h. This method has shown certain advantages over traditional intravesical chemotherapy.
3.4 Treatment approach for Tis
Tis is categorized as NMIBC, but it typically presents as poorly differentiated and highly malignant. Tis poses a higher risk of muscular infiltration compared to Ta and T1 bladder tumors and often coexists with these types or with MIBC. It is also considered a risk factor for a poor prognosis.
The standard treatment for Tis begins with TURBt, followed by adjuvant BCG intravesical immunotherapy. If a patient is unable to tolerate BCG instillation, intravesical chemotherapy may be considered as an alternative.
It is important to note that TURBt alone cannot cure Tis. BCG instillation shows a higher complete response rate (72%–93%) compared to intravesical chemotherapy (48%). It is significantly more effective in reducing the risk of tumor recurrence and progression. Despite the high response rates, about 10%–20% of cases that achieve complete remission with BCG may eventually progress to MIBC.
During BCG instillations, cystoscopy and urine cytology are performed regularly every 3–4 months. If complete remission is not achieved within 9 months of BCG treatment, or if there is tumor recurrence or progression, radical cystectomy is typically advised. In cases where Tis coexists with MIBC, radical cystectomy is often the recommended course of action.
3.5 Treatment options for post-TURBt recurrent tumors
Re-TURBt is recommended in NMIBC patients who relapse after intravesical chemotherapy. After the second surgery, patients can opt to try a new intravesical chemotherapeutic agent for another regimen of intravesical instillation or continue with BCG instillation.
For patients with repeated recurrences or multiple lesions, the recommended treatment is BCG intravesical instillation or radical cystectomy. Patients exhibiting the following conditions are considered to have BCG-refractory bladder cancer, and radical cystectomy is recommended: Progression to MIBC during the follow-up period; progression to high-grade NMIBC within 3 months of starting BCG instillation; Tis discovered within 3–6 months posttreatment; progression to high-grade NMIBC during or after BCG instillations.
3.6 Treatment protocol for patients with positive urine cytology but negative cystoscopy and imaging
In cases where patients exhibit positive urine cytology post-TURBt but have negative results in cystoscopy and imaging examinations, a thorough evaluation is necessary. This includes: Performing a random biopsy under cystoscopy; conducting urine cytology examination and imaging tests to check for the presence of an upper urinary tract tumor; and undertaking ureteroscopy, if deemed necessary.
If the random biopsy pathology confirms tumor presence, BCG intravesical instillation is recommended. Upon achieving a complete response, regular administration of intravesical instillation is necessary. If intravesical immunotherapy is ineffective or there is only partial response to the treatment, total cystectomy, switching to different instillation drugs, or considering experimental drugs still in clinical trials, are the available options. If a urine sample from the upper urinary tract is positive for tumor cells, and both ureteroscopy and imaging confirm the presence of an upper urinary tract tumor, the treatment should align with the standard protocol for upper urinary tract tumors. If both the random biopsy and the upper urinary tract examination yield negative results, then it is advisable to continue with regular follow-up intervals.
3.7 Follow-up of NMIBC patients
Ultrasound is frequently used for follow-up examination but is not a standalone method. Cystoscopy is the first-line method for regular check-ups in NMIBC patients. If suspicious lesions are observed on the bladder mucosa, a biopsy should be conducted for histology. When necessary, urine cytology, computed tomography (CT)/CT urography (CTU), magnetic resonance imaging/MR urography, among other examinations, can be performed additionally, but none of these examinations can completely replace the need for cystoscopy.
It is recommended that all NMIBC patients undergo the first cystoscopy within 3 months post-TURBt. If initial fulguration is deemed inadequate or if rapid tumor progression is anticipated, cystoscopy can be performed at an earlier time.
Low-risk NMIBC patients undergo cystoscopy within 3 months after surgery. If the initial cystoscopy is negative, a second cystoscopy is recommended 1 year after surgery, followed by annual examinations until the fifth year post-TURBt.
High-risk NMIBC patients are recommended to undergo cytology and cystoscopy every 3 months for the first 2 years, and then once every 6 months from the third year, and annually for life from the fifth postoperative year. Annual upper urinary tract examination (CTU examination) is also advised.
The follow-up plan is tailored based on the patient's individual prognostic factors and general condition, falling between the regimens for low- and high-risk patients. Identification of recurrence during follow-up necessitates re-evaluation of the postoperative follow-up plan according to the new circumstances.
If patients have positive urine cytology but no tumors are found during cystoscopy, additional diagnostic procedures including random biopsy, fluorescence/NBI cystoscopy-guided biopsy, CT/CTU (to rule out upper urinary tract tumors), and urethral prostate biopsy are recommended.
This English version was translated from the Chinese version, “Guidelines for Diagnosis and Treatment of Tumor and Blood Related Diseases (version 2022)” released by the General Office of the National Health Commission of the People's Republic of China. The copyright of the English version has been obtained. If there is any conflict in the information, the Chinese version shall prevail. See the Chinese version on the website of the National Health Commission of the People's Republic of China.
2024 The Authors. UroPrecision published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.
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