Clinical advances in the treatment of bladder cancer.

Overview bladder cancer is a malignant tumor that occurs in the mucous membranes of the bladder.
is the most common malignant tumor in the urinary system and one of the ten most common tumors in the whole body.
first in the incidence of genitourinary tumors in China, and second only to prostate cancer in the West.
bladder cancer is a huge social burden, with more than 430,000 men and women diagnosed with bladder cancer each year, with a high incidence of 50 to 70 years of age, three to four times the incidence of males and three to four times that of women, and nearly 170,000 people worldwide die from the disease each year.
Bladder cancer has many related risk factors, smoking is currently the most certain risk factor for bladder cancer, 30% to 50% of bladder cancer caused by smoking, smoking can increase the risk of bladder cancer 2 to 6 times, with the length of smoking, the incidence of bladder cancer also increased significantly.
another important risk factor for disease is related to a range of occupational or occupational exposures.
has now been confirmed that aniline, methamphetamine, 2-amine, 1-amine are carcinogens of bladder cancer, long-term exposure to such chemicals increased the probability of bladder cancer, occupational factors caused by bladder cancer patients accounted for about 25% of the total number of bladder cancer patients.
bladder cancer is a heterogeneous disease associated with a variety of clinical outcomes.
urine cortical cancer (UC), which was often referred to as cell carcinoma, is the leading histological type in the United States and Europe.
UC originated in the upper urinary tract (i.e., the kidneys, urethra, and urethra).
tumors that invade the urine muscle are called muscle-immersive bladder cancer (MIBCs) and have a higher tendency to spread to the lymph nodes and other organs.
non-muscle immersive bladder cancer (NMIBC) includes different entities, including in-place cancer (CIS), nipple-like non-invasive tumors, and invasive nipple-like tumors that invade the intrinsic layer.
NMIBC accounts for about 70 per cent of newly diagnosed bladder cancer and is one of the most expensive malignant tumours for treatment and care, taking into account the need for repeated endoscopic assessment and removal.
5-year survival rate for patients with NIMBC is about 90%.
about 15% to 20% of NMIBC progression to MIBC, CIS and high-level papyroid tumors are more likely to progress to MIBC.
5-year OS rate is about 60% to 70% in MIBC patients, about 10% of UC patients have diseases other than bladder, and the associated five-year OS rate is 5% to 30%.
treatment of muscle-immersive bladder cancer accounts for about 20% of new diagnoses of bladder cancer.
Despite a root-and-treat bladder removal (RC) and pelvic lymph node cleansing, about 50 percent of patients end up with tumors in the distance due to spread micro-metastasis.
, the combination of systematic therapy and topical therapy plays a key role in reducing recurrence rates.
new assisted chemotherapy as the standard of care: the new assisted chemotherapy based on cisplatin was first tested as a potential treatment strategy for MIBC in the 1980s.
Scher et al. treated 50 MIBC patients with methotrexate, changchun base, amycin and cisplatin (MVAC), and 30 others were subsequently treated with RC.
33% of patients treated with RC received a pathological complete response (pCR), while another 17% received a lower pathological T2 (pT2) tumor classification and a negative lymph node status.
, new assisted chemotherapy (NAC) reduced MIBC phases were associated with improved survival.
THE BA0630894 trial is the largest NAC study ever completed.
the trial, 976 patients received new auxiliary cisplatin, methotrexate and chrysanthyl (CMV) or did not receive NAC prior to RC.
8 years of medium follow-up, the 10-year survival rate can be increased from 30% to 36% with the new auxiliary CMV (risk ratio, 0.84; 95% CI, 0.72-0.99; P=0.037).
SWOG-8710 trial (a comparative trial of simple bladder excision in patients with local late-stage bladder cancer and a new assisted M-VAC-bladder excision) randomly assigned 317 patients to receive three cycles of MVAC, followed by RC and RC treatment alone.
, disease-specific survival rates were increased by the use of NACs (HR, 0.60; 95% CI, 0.41-0.82; P-0.0) compared to no NAC. 02), 5 years OS has a trend of improvement (57% vs 45%; HR, 0.75; 95% CI, 0.57-1.00; P s 0.06).
, new complementary chemotherapy based on cisplatin has become the standard of care for eligible MIBC patients.
a new complementary treatment strategy for patients with cisplatin insociance: Although cisplatin-based NAC is recognized as a peri-surgical treatment, about 50% of MIBC patients are insatiable due to age-related or disease-related risks.
Galsky et al. defined cisplatin indebtedness as meeting one of the following criteria: performance status of the Oriental Tumor Co-group, impaired renal function, creatinine removal rate (CrCl) of 60mg/min/1.73m2, Level III heart failure of the New York Heart Association, general term standard for adverse events (version 4) and level 2 hearing loss, and general term standard for adverse events (version 4) for neuropathy.
kapta-gasitabin (GCa) is a weakened alternative to GC in mUC and has been studied in retrospective analyses in several MIBC patients, where the pCR rate was lower and the hematological toxicity increased in phase 2 trials of single-arm yew alcohol, carptonine and gisectabin or nanoparticles in combination with cistaminol, carptonine and gisectal.
for this reason, the National Comprehensive Cancer Network guidelines do not recommend peri-surgical non-cisplatin chemotherapy.
For patients with CrCl:40 mg/min/1.73m2, a dose of cisplatin (35 mg/m2 on day 1 and 2) may be an alternative to good tolerance and clinical activity, but no randomized studies have been conducted.
use of immunosuppressants (ICIs) is a key emerging treatment strategy, and PD-1/PD-L1 inhibitors have been approved for use in first- and second-line treatments in late-stage UC.
based on the safety and effectiveity of these therapies for patients with advanced diseases, an extended study of their applications in new complementary therapies, complementary treatments, and bladder retention.
PURE-01 (New Auxiliary Pembrolizumab treatment for myotrophic urethroid bladder cancer; NCT02736266) is a single-arm Phase 2 trial, the first single dose of ICI study under new auxiliary conditions, in which 50 MIBC patients received pembrolizumab.
in this new study design, which includes patients who do not consider cisplatin, given three cycles of pembrolizumab before RC, and MVAC (ddMVAC), which is given in a dose-intensive manner prior to surgery, is available for patients who experience early disease progression.
46 patients (92%) were considered eligible for cisplatin treatment and 4 patients underwent Sequentium MVAC chemotherapy as a result of the early progress of the disease using pembrolizumab.
the entire patient queue, 21 patients (42%) achieved pCR and 27 patients (54%) had pT2N0 down to 10.
it is worth noting that the pCR rate of patients with a combined positive score (CPS) of 10 was measured according to the percentage of PD-L1-positive tumors and tumor-immersed immune cells, which was higher than that of patients with CPS-lt;10 (54.3 percent to 13.3 percent).
study of single dose ICI under new complementary treatment conditions is shown in the figure.
1: Another potential strategy in clinical trials of immunotherapy for myo-immersive bladder cancer is to conduct double immuno-checkpoint blocking in patients treated with cisplatin insuperance during peri-surgical systems.
combined inhibition of PD-1/PD-L1 and CTLA-4 may lead to an increased immune response, as their mechanisms of action for T-cell activity and effect T-cell response complement each other.
, biICIs have become the standard treatment for other solid tumors, such as melanoma and renal cell carcinoma.
first report on the new auxiliary dual ICIs, the university gave durvalumab combined tremelimumab to patients who did not meet the cisplatin condition of cT2-cT4aN0M0.
of the 21 patients who received a bladder excision, 9 (43%) had pCR and 2 had non-muscular leaching cancer.
resistance to co-medication was good, with 17 percent of patients developing level 3 immuno-related adverse events (irAEs), most commonly hepatitis.
also studied Ipilimumab plus nivolumab (14 cT3-cT4N0, 10 cN plus) in early clinical trials in MIBC patients.
54% of patients had level 3 or 4 irAEs, and 6 patients stopped treatment after 2 cycles.
10 (45%) of the 22 patients who received a bladder excision received pCR, and 3 patients had non-muscular leaching cancer.
larger randomized trials are needed to determine whether the new admissive double immune checkpoint blocking works in MIBC treatment.
improves prognostics in patients with cisplatin: Although cisplatin-based chemotherapy combined RC can improve patient survival, for some patients, residual cancer cells remain.
, Bhindi et al. found in a retrospective analysis of MIBC patients that patients treated with NAC had poor disease control and survival rates in patients with residual cancer.
for this subgroup of patients with NAC, the invasive nature of the disease requires optimized cisplatin-based chemotherapy.
possible option is to implement chemotherapy immunotherapy based on the immunomodulation properties of chemotherapy (Figure 1A).
Hoimes et al. demonstrated for the first time the anti-tumor activity and controllable toxic histological cancer of the new auxiliary chemical immunotherapy in phase 1b/2 trials using pembrolizumab and GC in patients with cT2-cT4aN0M0 UC/hybrid.
of the 40 assessable patients, 1 did not receive RC treatment due to severe adverse events (plate plateboard reduction cyanosis).
107 patients had 11 level 3 or 4 adverse events, the most common being hyponamicemia, thromboembolism, and renal insanity.
the pathological non-muscle immersion rate was 60%, and in the 14-month mid-follow-up, the estimated 12-month recurrence-free and disease-specific survival rate was 80% and 97%, respectively.
, Gupta and others evaluated the efficacy of the new aids nivolumab combined GC and RC in MIBC patients.
their report, 41 patients (cT2N0, 90%; cT3N0, 7%, cT4N1, 3%), pathological decline (spT1N0) and pCR rates were 66% and 49%, respectively.
in terms of safety, 20 percent of patients had level 3 and 4 adverse events, mainly due to chemotherapy, including plate plate plate reduction, nexual granulocyte reduction, and renal insexuality.
currently has three ongoing random Phase 3 studies of cisplatin-based new complementary chemotherapy immunotherapy: nivolumab (ENERGIZE, NCT03661320), durvalumab (NIAGARA, NCT03732677), pembrolizumab (KEYNOTE-866, NCT03924856).
potential solution for optimizing cisplatin-based NACs is to add ICI to admission settings (Figure 1C).
first reported study of this method, atezolizumab (IMvigor010, NCT02450331) did not reach the primary endpoint of improving disease-free survival.
three other phase III trials are currently under way, including the Pembrolizumab Comparison Observation Group (ambassar, NCT03244384), durvalumab (NIAGARA) and nivolumab vs placebo (CheckMate274, CT02632409).
treatment of advanced urethra skin cancer UC consists of local late UC and mUC and is generally considered an incurable disease.
so far, cisplatin-based chemotherapy is still the first-line treatment standard for late UC.
in patients who believe that the risks of cisplatin-based chemotherapy outweigh the potential benefits, are replaced by carabtin-based treatment options.
treatment options for late-stage UC have traditionally been limited.
over the past five years, an in-depth understanding of UC biology has contributed to a number of therapeutic advances, including ICIs, fibroblast growth factor inhibitors (FGFR) inhibitors, and antibody-coupled drugs (ADCs).
schedule for approving these new treatments is shown in Figure 2.
Figure 2: Platinum-based chemotherapy is still a first-line option in the approval schedule for new therapies for advanced urethroid skin cancer: the effects of cisplatin-based combination chemotherapy on improving survival rates in patients with bladder cancer were first confirmed in the early 1990s, when MVAC improved survival rates better than cisplatin alone.
use of MVAC is limited by toxicity, including neural granulocytosis, mucositis and peripheral neuropathy, with a mortality rate of 3% to 4%.
, other options, such as GC and ddMVAC, have been studied.
phase 2 study, GC had clinical activity and better toxicity characteristics similar to MVAC.
then, the Phase 3 trial, although not designed as a non-poor efficiency study, was objectively efficient (ORR) similar (GC and MVAC were 49% and 46%, respectively), and the OS of the two schemes was similar.
ddMVAC also showed better tolerance than classic doses of MVAC, and although the two options did not differ significantly in OS outcomes, they experienced persistent diseases.