The Diagnosis and Treatment of Patients with Bladder Carcinoma
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Background: In Germany, bladder carcinoma accounts for 3–4 % of all malignant tumors. New study findings in the fields of endoscopy, surgery, and systemic therapy have led to multimodal treatment approaches for bladder cancer that can prolong overall survival and improve the affected patients’ quality of life.
Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, with special attention to the German Clinical Practice Guideline on the Early Detection, Diagnosis, Treatment, and Continuing Care of Bladder Carcinoma, along with data available on the websites of the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The bladder carcinoma guideline of the Onkopedia guidelines program was used as well.
Results: 75% of all urothelial carcinomas are diagnosed in the non–muscle-invasive stage. These carcinomas should be resected via the endoscopic transurethral approach whenever possible. Next, depending on the patient’s risk profile, intravesical therapy may be needed. Patients with carcinoma in the muscle-invasive stage should be given multimodal treatment, including radical cystectomy with urinary diversion and perioperative systemic therapy; alternatively, bladder-preserving chemoradiotherapy can be offered in selected cases. For patients with metastatic bladder carcinoma, immunotherapy with checkpoint inhibitors has become well established for first- and second-line therapy alongside classic cytostatic treatment and has been shown to prolong patients’ lives significantly. The administration of checkpoint inhibitors can prolong the overall survival of patients with metastases to 15–17 months.
Conclusion: The treatment of bladder carcinoma in all stages calls for interdisciplinary collaboration to ensure the provision of effective, individual multimodal treatment.
Bladder carcinomas account for 3–4% of all malignant tumors in Germany. They occur at the age peak over 70 years. Bladder cancer is the fourth most common tumor in men in Germany, and 14th in women (1). In 2016, a total of 16,470 people were diagnosed with invasive and 13,500 with non-invasive neoplasms of the bladder. These figures do not include non-muscle-invasive bladder carcinomas with a carcinoma in situ or papillary Ta tumors (Figure 1) (1). Diagnosis is usually prompted by the main symptom, hematuria. Smoking is one of the most important risk factors (1).
Invasive urothelial carcinomas usually develop from severe urothelial dysplasia or in situ carcinoma. They may occur multifocally. Mutations that are associated with deoxyribonucleic acid (DNA) mismatch repair or other hereditary tumors are detected in approximately 20% of patients. A distinction is made between at least five different mutation signatures with prognostic relevance (2).
The treatment options for bladder cancer have changed significantly, especially in the metastatic stage, since the 2016 German S3 guideline, hence an updated version was published in May 2020 (3).
This review article is based on the S3 guideline “Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms” (early detection, diagnosis, treatment and follow-up of bladder carcinoma) of the German Cancer Society, German Cancer Aid, and the Association of the Scientific Medical Societies in Germany (AWMF) (3), as well as the guideline “Blasenkarzinom (Urothelkarzinom)” (bladder carcinoma [urothelial carcinoma]) from the Onkopedia guideline program (4). In addition, a literature search on immunotherapy was performed in PubMed using the search terms “(checkpoint or atezolizumab or pembrolizumab or nivolumab or durvalumab or avelumab or ipilimumab or tremelimumab) and bladder cancer” as well as a review of the websites of the Food and Drug Administration (FDA) and the European Medicines Agency (EMA).
Primary diagnosis of bladder carcinoma
The first sign of bladder cancer is generally painless micro- or macrohematuria, which may be combined with nonspecific irritative symptoms such as dysuria or pollakiuria. Classic symptoms of tumor disease do not appear until advanced stages. Tumor cells may be detectable in a urine cytology examination. The absence of such cells does not exclude a bladder tumor. The specificity for low-grade and high-grade carcinomas is overall 90–100%, while sensitivity is only 20–50% (5). Therefore, the method is not suitable for screening. Molecular tumor markers have not been established for clinical practice as yet. In the case of a well-founded suspicion, (fluorescence-assisted, if needed) white light cystoscopy is required as a standard method in the primary diagnostic work-up and always includes an evaluation of the complete bladder due to the possibility of multilocular occurrence. If the urothelium is abnormal, subsequent transurethral bladder resection (TURB) is both diagnostic and therapeutic in nature (e1). If no bladder carcinoma is visible and the symptoms remain suspicious for carcinoma, a further diagnostic work-up of the upper urinary tract is carried out.
Non-muscle-invasive bladder carcinoma
Transurethral bladder tumor resection
A total of 75% of all bladder carcinomas (carcinoma in situ, Ta, and T1) are diagnosed at the non-muscle-invasive stage and can be detected only in mucosal and submucosal layers. If technically feasible, small bladder tumors should undergo transurethral, and thus therapeutic, resection in toto if possible. Larger bladder tumors require fractional resection, including the detrusor muscles (3, e1). Fluorescence-assisted TURB with hexaminolevulinate should be performed as an adjunct in patients with a history of multifocal tumors or high-grade tumors, as well as in the case of suspected carcinoma in situ (6). Incomplete resection, pT1, or high-grade findings in bladder tumors require transurethral resection (3).
Intravesical instillation in the bladder and follow-up care
The probability of recurrence or progression of non-muscle-invasive bladder cancer is estimated according to the point-based risk stratification score of the EORTC (European Organisation for Research and Treatment of Cancer) (7) (Table 1). This score is calculated from information on the number of tumors, tumor size, prior recurrence rate, T stage, and grading (Table 2) (7, 8). Further follow-up care or additional intravesical instillation treatment is based on the EORTC risk group (9). Urothelial carcinoma patients in the low-risk group should receive a single early instillation following TURB, but not longer-term adjuvant instillation of intravesical chemotherapy. In contrast, the EORTC recommends instillation of intravesical chemotherapy with mitomycin C or instillation therapy with bacillus Calmette-Guérin (BCG) for patients at intermediate risk (10). Patients at high risk according to the EORTC should receive BCG instillation therapy for at least 1 up to a maximum of 3 years (e2). In the case of early recurrence or tumor persistence and a high-risk constellation in non-muscle-invasive bladder carcinoma following BCG induction therapy, radical cystectomy with urinary diversion should be performed (11). Only in the case of patient refusal or inoperability for other reasons can this be substituted by transurethral resection followed by radio(chemo)therapy (12).
Muscle-invasive bladder carcinoma
The diagnosis of muscle-invasive bladder carcinoma includes TURB and histological confirmation, classical laboratory tests, and imaging in the form of computed tomography (CT) of the chest, abdomen, and pelvis including urographic phase. Alternatively, one can select magnetic resonance imaging (MRI) of the abdomen and pelvis. Cranial computed tomography or skeletal scintigraphy are not required in the primary diagnostic work-up and are indicated only in symptomatic patients (3).
Prior to radical cystectomy and as part of a multimodal concept, patients with muscle-invasive bladder carcinoma (≥ cT2) should be informed in a multidisciplinary manner about the possibilities of neoadjuvant or adjuvant chemotherapy, taking into account their individual situation and risk. The combination of radical cystectomy and perioperative chemotherapy can improve overall survival at 10 years by an absolute rate of 5–10% (13). The treatment concept should always be discussed and defined in a multidisciplinary approach. Unfortunately, neoadjuvant and adjuvant cisplatin-containing chemotherapy have never been compared in a randomized setting, meaning that the different options can only be weighed up by individually analyzing the known data from the various studies. Advantages of the neoadjuvant approach include good preoperative general condition and patient compliance, as well as early treatment of possible micrometastases (13, e3). A factor that speaks for the adjuvant approach is the more accurate postoperative staging, which obviates the need for chemotherapy in a proportion of patients since adjuvant chemotherapy is recommended only in those with stage ≥ pT3 or lymph node involvement (13, e4). Current phase III trials are evaluating the benefit of neoadjuvant and adjuvant treatment with checkpoint inhibitors and combinations of immunochemotherapy (NCT03661320, NCT02632409, NCT02450331).
The gold standard of treatment for muscle-invasive bladder carcinomas is radical cystectomy with curative intent and appropriate urinary diversion. The surgical challenge is to preserve—insofar as technically feasible and oncologically justifiable—continence and potency to the greatest extent possible (function-preserving radical cystectomy) (14, 15). Complete continence is preserved in 70–93% of cases undergoing orthotopic bladder replacement, while erectile function is preserved in 33–100% depending on the surgical technique and tumor stage (14, 15). Radical cystectomy includes pelvic lymphadenectomy in the region of the iliac arterial axis. In men, cystectomy involves removal of the bladder, prostate, and seminal vesicles; in women, the bladder, uterus, and parts of the anterior vaginal wall, depending on tumor location, are removed. The choice of urinary diversion following cystectomy depends on tumor stage, age, general condition, and patient preference. Alternatively, a continent orthotopic bladder replacement using an ileal neobladder, a urostomy (ileal conduit), or a catheterizable pouch can be created (16, e5).
In the case of preoperative contraindications to cisplatin-containing chemotherapy, primary cystectomy should be aimed for within 3 months of diagnosis. Further delays negatively affect overall survival, although the precise temporal relationship here has not been elucidated (17). Long-term (10-year) survival after cystectomy alone ranges, depending on stage, between >90% for pT1 and <40% for pT4 tumors. Lymphatic metastasis significantly worsens the disease prognosis, with long-term survival rates < 20% (18, 19). In the case of local incomplete resection (R1/R2), postoperative radio(chemo)therapy can be performed, although there are no prospective studies on this approach (e6).
Organ-preserving, multimodal therapy
Multimodal, primary organ-preserving treatment—comprising initial TURB followed by simultaneous radiochemotherapy—is an alternative to radical cystectomy with curative intent for patients with muscle-invasive bladder carcinoma (20, 21). Patients in whom no tumor is detected at restaging are closely followed-up. In the case of residual muscle-invasive cancer or recurrence in the bladder, subsequent salvage cystectomy is a possible curative treatment option. This concept should be offered to patients with locally confined muscle-invasive urothelial carcinoma (cT2-4a cN0 cM0) if they are unsuitable for radical cystectomy or desire an alternative to radical surgery. Patients with early-stage bladder cancer (cT2 cN0 cM0) without hydronephrosis or an associated carcinoma in situ in whom initial TURB has resulted in the most complete endoscopic tumor removal (R0) possible, have a good prognosis. Radiosensitization in concurrent radiochemotherapy should be performed with cisplatin-based chemotherapy or a combination of 5-fluorouracil and mitomycin C (e7, 22). Experience and long-term results are now available from monocentric series as well as prospective clinical treatment optimization studies of primary organ-preserving treatment concepts. Complete remission rates of between 60% and 90% after TURB plus radiochemotherapy have been reported, as have 5-year survival rates of between 40% and 75% with bladder preservation in approximately 80% of surviving patients (23).
Metastatic urothelial carcinoma
Median overall survival without systemic treatment is 3–6 months at the metastatic stage, meaning that primary systemic treatment should be performed if the patient’s general condition permits. Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status scales, as well as visceral metastases (lung, liver, and bone) are independent prognostic factors for survival after first-line chemotherapy (24, e8). The classic first-line therapy is four to six cycles of cisplatin-based chemotherapy. This includes combination gemcitabine and cisplatin (Gem/Cis) or the MVAC regimen (methotrexate, vinblastine, adriamycin, and cisplatin). The most important prospective randomized phase III trial investigated the Gem/Cis versus MVAC combination in 405 patients with metastatic or locally advanced unresectable urothelial carcinoma. Results showed no significant difference in median overall survival for Gem/Cis (14.0 months) and MVAC (15.2 months) (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: [0.88; 1.34]; p = 0.66). Although the number cases in this study was designed merely to demonstrate a superiority in survival for Gem/Cis compared to MVAC, the virtually identical survival curves have resulted in a general acceptance of this combination therapy as the new standard due to its fewer side effects (25). The first follow-up is performed after two or three cycles of the abovementioned chemotherapies in order to document treatment response (3).
Between 30 and 50% of patients have one or more contraindications to cisplatin use. Criteria for cisplatin-ineligible patients have been established in an international consensus (Box) (26). If only creatinine clearance is decreased to between 40 and 60 mL/min, the risk of toxicity can be reduced by fractionating the cisplatin dose (3). If other criteria speak against cisplatin, the carboplatin/gemcitabine combination is an alternative. However, a prospective phase II/III study demonstrated that, with a median overall survival of less than 10 months, carboplatin- compared to cisplatin-containing combination chemotherapies are inferior (27).
Checkpoint inhibitors to PD-1 (programmed cell death protein 1) or PD-L1 (programmed death ligand 1) have ushered in a new era of systemic therapy. For first-line cisplatin-ineligible patients, the checkpoint inhibitors atezolizumab, a PD-L1 antibody, and pembrolizumab, a PD-1 antibody, have been approved to date. According to RECIST (response evaluation criteria in solid tumors), the objective response rates for pembrolizumab and atezolizumab in single-arm, non-controlled phase II trials were 24% and 23%, respectively, with complete remission rates of 5% and 9%, respectively. The response rate for pembrolizumab correlated with the level of PD-L1 expression. However, this did not hold true for atezolizumab (28, 29). Median overall survival for the total cohort was 18.5 and 15.9 months, respectively (Table 3) (28, 29, 30).
The method of PD-L1 determination in tumor material involves various primary antibody and immunohistochemical scores, the CPS (combined positive score), or the IC score (PD-L1 on immune cells). This hampers comparability between studies.
Based on the results of the phase III KEYNOTE 361 trials and the recently published data from the IMvigor 130 study, the EMA restricted the approval of the two checkpoint inhibitors in terms of first-line treatment of cisplatin-ineligible patients to those with high PD-L1 expression (atezolizumab IC ≥ 5%; pembrolizumab CPS ≥ 10) (31). In studies published to date, between 23% and 30% of patients exhibit this expression. In summary, cisplatin-ineligible patients can only be treated with the checkpoint inhibitors atezolizumab or pembrolizumab in the first-line setting if they have a positive PD-L1 status (Figure 2). In conclusion, due to the lack of predictive markers, it is not possible to predict whether chemotherapy or immunotherapy is the better alternative for the individual patient.
In the studies with pembrolizumab and atezolizumab, grade 3–4 adverse events occurred with a probability of 15% and 16%, respectively. The most common serious adverse events included fatigue, diarrhea, pruritus, and rash (Table 4). Overall, 5% and 8% of patients, respectively, were forced to discontinue treatment due to immune-mediated toxicities (28, 29). However, immune-mediated adverse events can be fatal in some cases (eBox) (32). Therefore, it is essential to provide detailed patient education in order to sensitize patients to possible adverse events and, in the case of known autoimmune disease, to take a critical approach when making the indication.
If metastatic urothelial carcinoma progresses under or after cisplatin-containing chemotherapy, immunotherapy with a PD-(L)1 inhibitor is favored in the second-line setting regardless of PD-L1 expression (3). The two-arm, randomized phase III KEYNOTE-045 trial demonstrated, for the first time, a superiority for immunotherapy over chemotherapy in the second-line treatment of metastatic urothelial carcinoma with regard to overall survival. A total of 542 patients were treated with either pembrolizumab or chemotherapy (vinflunine, paclitaxel, or docetaxel). Pembrolizumab significantly prolonged median overall survival as the primary endpoint compared to monochemotherapy (10.3 versus 7.4 months, p = 0.0004, HR: 0.70) (33). In a prospective randomized phase III trial (IMvigor211), atezolizumab was also compared with vinflunine or a taxane. The primary endpoint was overall survival in the PD-L1-positive subgroup (IC2/3). No prolongation of overall survival was observed (atezolizumab 11.1 versus vinflunine or taxane 10.6 months, p = 0.41, HR: 0.87) (34). A single-arm, nonrandomized phase II study (CheckMate 275) reported a remission rate of 19.6% (95% CI [15.0; 24.9]) for nivolumab. Overall survival was 8.7 months (95% CI [6.05 not reached]) for the total group (35). In summary, the checkpoint inhibitors pembrolizumab, atezolizumab, and nivolumab are approved in Germany for second-line treatment following prior platinum-containing treatment irrespective of PD-L1 status (eTable).
In the case that checkpoint inhibitors are contraindicated, second-line chemotherapy with vinflunine can be proposed as an alternative. A two-arm, randomized phase III trial compared vinflunine with best supportive care (BSC). The prolongation of median overall survival by 2.6 months was statistically significant only in the per-protocol analysis (HR: 0.77 [0.61; 0.99], p = 0.04]) (36). Prognostically unfavorable factors of second-line chemotherapy were identified to be poor general condition (ECOG ≥ 2), liver metastases, low hemoglobin level, and short interval since the end of first-line therapy. With at least two of these risk factors, median overall survival was only 1.7 months, whereas it was 14.2 months without risk factors (36, 37). In summary, checkpoint inhibitors are preferred over chemo-monotherapy for second-line treatment after cisplatin-containing combination therapy, irrespective of PD-L1 status (Figure 2).
The introduction of checkpoint inhibitors heralds the start of innovative development in the treatment of advanced urothelial carcinoma. Chemo-immunotherapy combinations with atezolizumab and Gem/Cis or chemo-immune sequences with Gem/Cis followed by avelumab could fundamentally alter the first-line treatment of metastatic urothelial carcinoma in the near future (31, 38). In addition, numerous trial designs have been initiated with new classes of agents in the second- and third-line setting. These include antibody-linked cytostatic drug such as enfortumab vedotin and fibroblast growth factor receptor (FGFR) targets such as erdafitinib. Both drugs showed high remission rates of over 40% in second- and third-line monotherapy (39, 40). The FDA has approved enfortumab vedotin for patients following prior treatment with checkpoint inhibitors. Erdafitinib was also approved by the FDA for patients with FGFR2- and FGFR3-altered advanced urothelial carcinoma diagnosed with associated polymerase chain reaction (PCR) testing.
For metastatic urothelial carcinoma, a phase III study—the JAVELIN Bladder 100—has now been published (e9); this trial investigated maintenance therapy with a checkpoint inhibitor, avelumab, in 700 patients in whom the tumor had shown a response to, or at least no progression under, the previous treatment. Since there was an overall survival benefit of 7.1 months (21.4 versus 14.3 months) for the avelumab-treated group, treatment with avelumab following platinum-containing chemotherapy has been approved by the EMA since January 22, 2021.
Conflict of interest statement
Prof. de Wit received congress fees and travel cost reimbursement from Pierre Fabre, Astellas, and BMS. She has received speaker’s fees from AstraZeneca, MSD, Abbvie, ASCO Today, and ESMO Today. Study support (external funding) was made available to her by AstraZeneca, MSD, Pierre Fabre, BMS, MorphoSys, Pfizer, Ipsen, Novartis, Nucana, and Merck.
Prof. Retz has received honoraria for consultancy services (advisory board) from MSD, Roche, BMS, Pfizer, and AstraZeneca. Congress fees were reimbursed to her by Janssen-Cilag. She has received speaker’s fees from MSD, BMS and Roche.
Prof. Gschwend received honoraria for consultancy services (advisory board) from Roche, MSD Pharma, BMS, and Merck. He was reimbursed for congress fees and travel expenses by Roche. He received speaker’s fees from Roche, MSD, and Merck.
Prof. Rödel declares that no conflict of interest exists.
Manuscript data submitted 10 August 2019, revised version accepted 29 September 2020.
Translated from the original German by Christine Rye.
Prof. Dr. Maike de Wit
Vivantes Klinikum Neukölln
Klinik für Innere Medizin – Hämatologie, Onkologie und Palliativmedizin
Rudower Str. 48, 12351 Berlin, Germany
Cite this as
de Wit M, Retz MM, Rödel C, Gschwend JE: The diagnosis and treatment of patients with bladder carcinoma. Dtsch Arztebl Int 2021; 118: 169–76. DOI: 10.3238/arztebl.m2021.0013
eReferences, eBox, eTable:
S3-Leitlinie Früherkennung, Diagnose, Therapie und Nachsorge des Harnblasenkarzinoms, Langversion 2.0,2020, AWMF-Registrierungsnummer 032/038OL. www.leitlinienprogramm-onkologie.de/leitlinien/harnblasenkarzinom (last accessed on 20 January 2021).
6 May 2020).
Department of Hematology, Oncology and Palliative Medicine, Vivantes Neukölln Hospital Berlin: Prof. Dr. med. Maike de Wit*
Department of Urology Klinikum rechts der Isarder Technical University Munich (TUM): Prof. Dr. med. Margitta M. Retz*, Prof. Dr. med. Jürgen E. Gschwend
Department of Radiotherapy and Oncology, University Hospital Frankfurt am Main:
Prof. Dr. med. Claus Rödel
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