I. Introduction: Radical cystectomy with regional pelvic lymph node dissection is the standard procedure for the treatment of invasive bladder cancer, with a good long-term prognosis for organ-confined bladder cancer and a high risk of local recurrence and distant metastases for non-organ-confined bladder cancer, of which only a minority of local recurrences occur while most develop distant metastases. The largest recent report is from the University of Southern California (USC), where radical cystectomy with regional lymph node dissection was used to treat invasive bladder cancer in 1054 cases with a median follow-up of 10.2 years and an overall 10-year recurrence-free survival rate of 66%; the 10-year recurrence-free survival rates were 78% and 76% for T2 and T3a lymph node negative patients, respectively; and T3b and T4 lymph node negative patients. The 10-year recurrence-free survival rates were 61% and 45% for stage T3b and T4 lymph node-negative patients, respectively; 246 patients (24%) had positive regional lymph nodes, with a 10-year recurrence-free survival rate of only 34%; the overall recurrence rate was 30% (311 patients), with distant metastases accounting for 22% (234 patients) and local pelvic recurrence accounting for only 7% (73 patients), with a median recurrence time of 12 months.
Another study reported 129 cases of T3a and T3b bladder cancer with a median follow-up of 13.6 years and overall 10-year recurrence-free survival and overall survival rates of 54% and 20%, respectively, for those with positive and negative lymph nodes (P = 0.003). The local recurrence rate was 9% (12 cases) and distant metastasis was 29% (37 cases).
The Memorial Sloan-Kettering Cancer Center (MSKCC), with a median follow-up of 7.5 years in 162 patients, reported that the ratio of the number of positive lymph nodes to the total number of lymph nodes cleared was more meaningful in determining local recurrence and survival than conventional lymph node staging. The 5-year overall survival and recurrence-free survival rates were 37.3% and 38.1%, respectively, for the less-than-25% group and 18.7% and 10.6%, respectively, for the greater-than-25% group, making lymph node density a meaningful prognostic factor in positive patients grouped by 25%.
A prospective multicenter study recommended expanded lymph node dissection as the standard procedure in 290 patients with T2 to T4 or T1G3 with 27.9% lymph node metastases and lymph node dissection superior to the inferior mesenteric artery with 43.1 +/- 16.1. The number of lymph nodes dissected was found to be 12.9% of all metastases above the aortic bifurcation, and expanded lymph node dissection surgery could improve the prognosis by more completely removing the possible metastases.
The above data suggest that the risk of distant recurrence is quite high in a significant proportion of patients, especially in patients with stage T3 or higher and positive lymph nodes. Therefore, theoretically, performing perioperative systemic chemotherapy can eliminate micro-metastases and improve the surgical outcome.
II. Overview of systemic chemotherapy for urothelial carcinoma of the bladder Cisplatin-based combination chemotherapy is the standard regimen for the treatment of metastatic urothelial carcinoma of the bladder. Studies have demonstrated higher remission rates and significantly improved survival with the MVAC regimen compared to cisplatin alone, CISCA (cisplatin, cyclophosphamide and adriamycin) and FAP (fluorouracil, interferon α2b and cisplatin). A phase III randomized clinical study by the European Organization for Research and Treatment of Oncology Genitourinary Oncology Cooperative Group showed that a high-dose MVAC regimen (HD-MVAC) with concomitant application of human recombinant granulocyte colony-stimulating factor (rhG-CSF) for patients with advanced uroepithelial carcinoma of the bladder had a median survival of 15.5 months, which was not significantly different from the median survival of 14.1 months with the conventional MVAC regimen A phase III randomized clinical study comparing GC (gemcitabine 1000 mg/m2 days 1, 8, 15; cisplatin 70 mg/m2 day 2) with conventional MVAC in 405 patients compared GC (gemcitabine 1000 mg/m2 days 1, 8, 15; cisplatin 70 mg/m2 day 2) with progression-free survival (9.1 vs. 8.2). The median survival was 13.8 months versus 14.8 months, with remission rates of 49% versus 46% and tumor progression times of 7.4 months, respectively, and similar results. The GC regimen was significantly more tolerable and safer than MVAC, although the results of this study do not indicate that the survival rates of the two regimens are indistinguishable. Although the results of this study do not indicate that survival rates are indistinguishable, the GC regimen has been widely accepted as the new standard of care for chemotherapy of metastatic urothelial carcinoma of the bladder due to its significantly reduced toxic effects and the overlapping survival curves of both regimens over 3 years. Recent updated data from the same clinical trial showed that the median survival was 14.0 versus 15.2 months, median progression-free survival was 7.7 versus 8.3 months, 5-year survival was 13.0% versus 15.3%, and 5-year progression-free survival was 9.8% versus 11.3% for GC versus MVAC, respectively, further supporting the use of GC as the standard chemotherapy for locally advanced or metastatic bladder urothelial carcinoma. epithelial cancer as a standard chemotherapy regimen.
Advantages and disadvantages of neoadjuvant chemotherapy Neoadjuvant chemotherapy is an adjuvant chemotherapy used before definitive local treatment (e.g. surgery or radiotherapy) and has been applied to breast, laryngeal, non-small cell lung, cervical, esophageal, rectal and prostate cancers to effectively improve survival and increase the likelihood of organ preservation. Here we discuss the advantages and disadvantages of neoadjuvant chemotherapy.
Before and after neoadjuvant chemotherapy, we can evaluate the changes of tumor by means of clinical examination to understand the sensitivity of tumor to chemotherapy and whether the tumor has a clinical downgrade; we can obtain pre-chemotherapy tumor specimens by biopsy and soon post-chemotherapy specimens by radical cystectomy, thus determining the histopathological changes of tumor before and after chemotherapy, and we can quickly judge the chemotherapy regimen before getting the long-term follow-up results effectiveness; certain information may be obtained through molecular biology studies of tumor tissues to assist in determining the sensitivity of the tumor to chemotherapy and to assist us in screening patients sensitive to chemotherapy; patients sensitive to neoadjuvant therapy, downstaged to pT0, may be considered for bladder preservation treatment options. Patients with good physical condition before surgery have high tolerance to chemotherapy; early chemotherapy can eliminate micro metastases as early as possible and avoid rapid growth of metastases; it can avoid the destruction of local vascular bed by surgery, which may be beneficial to chemotherapy.
The biggest disadvantage of neoadjuvant chemotherapy is that its toxic effect may delay the implementation of surgery, but randomized studies have shown that this delay does not affect the long-term treatment effect; neoadjuvant chemotherapy is based on clinical staging, unlike adjuvant chemotherapy after surgery which is based on pathological staging, and the error of staging may affect the selection of cases, too high clinical staging makes some low-risk cases with low staging receive unnecessary chemotherapy, too low Too high clinical stage makes some high-risk and high-stage patients do not receive proper treatment; so far there is no report suggesting that neoadjuvant therapy increases the difficulty and complications of surgery.
The results of the 1995 analysis by the Advanced Bladder Cancer Meta-Analysis Collaborative (ABCMC) showed that the initial clinical trials did not confirm that neoadjuvant chemotherapy improved survival, which was associated with small trial sample sizes, inconsistent chemotherapy regimens and drug doses, and poor local treatment control. randomized controlled trials of adjuvant therapy and analyzed data from 2688 patients from 10 of these trials. The results found that cisplatin single-agent neoadjuvant chemotherapy did not improve survival, but cisplatin-based combination chemotherapy regimens improved overall survival in patients with invasive bladder tumors (HR=0.87, 95% CI 0.78-0.98, p=0.016); the risk of death was reduced by 13%; 5-year survival was improved by 5% (1-7%), from 45% to 50%, and the risk of death was reduced by 13% in all subgroups. In 2005, the organization updated the data again to include 11 randomized controlled clinical trials including information on 3005 patients, and the analysis showed that cisplatin-based combination chemotherapy regimens improved overall survival (HR = 0.86, The results of this analysis showed that cisplatin-based combination chemotherapy improved overall survival (HR = 0.86, 95% CI 0.77-0.95, p = 0.003), corresponding to a 5% improvement in 5-year survival, and improved disease-free survival (HR = 0.78 95% CI 0.71-0.86, p < 0.0001), corresponding to a 9% improvement in 5-year disease-free survival. Of these, data from 11 clinical trials (2,605 patients) were analyzed and showed that neoadjuvant chemotherapy improved survival (HR= 0.90, 95% CI 0.82-0.99, p = 0.02), with 8 trials using a cisplatin-based combination chemotherapy regimen significantly improving 5-year survival (HR= 0.87, 95% CI 0.78 to 0.99, p < 0.02). 95% CI 0.78 to 0.96, p = 0.006), corresponding to a 6.5% (95% CI 2 to 11%) increase in 5-year survival, from 50% to 56.5%. Mention should be made of the largest randomized clinical trial published in LANCET in 1999, which enrolled 976 patients between 1989 and 1995, staged as T2 G3, T3, T4a, N0-NX, or M0, and treated locally with radical surgery or full-dose external radiotherapy. 485 patients were enrolled in the radical local treatment group, and 491 patients first received 3 courses of CMV neoadjuvant chemotherapy followed by radical radiotherapy. The results showed that the 3-year survival of the chemotherapy group was better than that of the radical group. The 3-year survival rate was found to be 55.5% in the chemotherapy group and 50.0% in the non-chemotherapy group, showing a difference of 5.5% (95% CI -0.5 to 11.0, p=0.075) between the two groups, which did not achieve the expected 10% improvement in 3-year survival; median survival was 44 months versus 37.5 months in the chemotherapy and non-chemotherapy groups, respectively. The 3-year disease-free survival rates were 46% and 39% for the two groups, respectively, p=0.019. The chemotherapy-related mortality rate was 1% and the radical cystectomy-related mortality rate was 3.7%. No residual tumor was found in 32.5% of radical cystectomy specimens after neoadjuvant chemotherapy (pT0). At follow-up to 7 years, the difference in survival between the two groups appeared statistically significant. Possible reasons for the lack of a statistically significant difference in 3-year survival in this trial are: the CMV regimen used was not the accepted standard chemotherapy regimen and chemotherapy outcomes may vary; 42% versus 43% of patients in the two groups received external radiotherapy as a local treatment modality, respectively, and it is uncertain whether radical external radiotherapy can achieve radical cystectomy, which may affect the improvement in survival with chemotherapy . In 2003, the New England Journal of Medicine reported a randomized clinical trial spanning 11 years, enrolling 317 patients with T2-T4a (AJCC 1992), randomized to either a radical cystectomy group or a three-course MVAC plus radical cystectomy group, with the aim of evaluating the effect of the standard MVAC regimen on survival and tumor regression. The results showed 5-year survival rates of 43% versus 57%, respectively (p=0.06,) with a median survival of 46 months versus 77 months in both groups at more than 8 years of follow-up. The percentage of residual tumor-free (pT0) specimens was 15% versus 38% in both groups (P<0.001), and neoadjuvant chemotherapy improved the percentage of residual tumor-free patients with a survival rate of 85% at 5-year follow-up for pT0 patients. There was no increase in the incidence of postoperative complications and no chemotherapy-related deaths. Neoadjuvant chemotherapy with paclitaxel with cisplatin prior to radical cystectomy achieved a 5-year survival rate of 51.92% , and 36.6% of those with pT0 pathology after radical surgery were associated with improved 5-year survival (93.33% versus 40.72%, p = 0.031) The effect of GC regimen neoadjuvant chemotherapy on survival of patients with urothelial carcinoma of the bladder has not been reported. V. Neoadjuvant chemotherapy and bladder-preserving surgery One of the advantages of neoadjuvant chemotherapy is that it allows rapid evaluation of tumor sensitivity to chemotherapy. By pathological examination of radical cystectomy specimens, 30-40% can be downgraded to pT0 and is associated with improved long-term survival, meaning that possible distant micro-metastases are similarly controlled. If invasive uroepithelial carcinoma of the bladder is treated with neoadjuvant chemotherapy or concomitant radiation therapy and the tumor is downstaged to pT0, is there still a need for radical cystectomy and can the bladder be preserved? The long-term efficacy of this treatment versus radical cystectomy has not been studied in a randomized controlled study, so it should only be used for patients who refuse or are not eligible for radical cystectomy at this time. In the 1998 MSKCC study, 111 patients with T2-3N0M0 bladder tumors treated with neoadjuvant chemotherapy with MVAC followed by transurethral resection (TUR) of the primary tumor site showed a reduction in stage to pT0 in up to 54% (60) of cases, of which 28 were followed up with TUR only, 15 with partial resection, and 17 with radical cystectomy. By a median 10-year follow-up, 32 (74%) of the 43 cases with preserved bladder survived, including 25 with intact bladder function, whereas only 11 (65%) of the 17 cases with radical cystectomy survived, which is an encouraging result and suggests that patients with MVAC chemotherapy-sensitive bladder tumors can be treated conservatively with preserved bladder without compromising survival. However, it is important to note that 24 of 43 (56%) of the bladder-preserving cases recurred and 6 of 13 died after radical cystectomy. In a similar report by Sternberg et al. in 2003, 104 patients with T2-T4,N0,M0 received 3 courses of neoadjuvant chemotherapy with MVAC and after re-staging, 52 had TUR, 13 had partial cystectomy and 39 had radical cystectomy. The 5-year survival rate was 69% in the partial cystectomy group compared to 38% in the radical cystectomy group at 45 months follow-up. 77 patients who had a step-down to T0-1 had a 5-year survival rate of 69% compared to 27 patients who remained above T2 after chemotherapy with a 5-year survival rate of 26%. The results suggest that patients can be selected for bladder-preserving surgery based on sensitivity to neoadjuvant chemotherapy, but the feasibility of this option requires further validation in randomized clinical trials. Radical cystectomy has been the standard of care for invasive uroepithelial carcinoma of the bladder in the United States, but for more than 10 years, many urologists outside the United States have been exploring ways to cure the tumor, preserve bladder function, and improve quality of life through a combination of chemotherapy, radiation therapy, and local conservative treatment. The Radiation Therapy Oncology Group (RTOG) has completed six prospective studies on the integrated treatment of bladder tumors, starting with a combination of chemotherapy, radiation and local conservative therapy for invasive uroepithelial carcinoma of the bladder, followed by radical cystectomy for failure. A total of 415 patients were enrolled, with a 5-year survival rate of approximately 50%, and bladder function was preserved in three quarters of those patients whose tumors were cured. The combination of these three modalities provides better results than radiotherapy or chemotherapy alone, with long-term survival rates approaching those of radical cystectomy, and can be used for first diagnoses of invasive uroepithelial carcinoma of the bladder, providing a viable alternative treatment for patients who do not wish to have their bladders removed and are eligible for close follow-up, but does not replace radical cystectomy. VI. Molecular biological methods to predict chemotherapy sensitivity Relying on traditional tumor staging and grading to determine prognosis is still the main means of clinical application nowadays, and the same approach is used to screen the sensitivity of tumors to neoadjuvant chemotherapy. If the sensitivity of tumor cells to chemotherapy can be detected by molecular biology methods before neoadjuvant chemotherapy is administered, chemotherapy can be selectively administered to avoid ineffective chemotherapy and side effects, conserve resources, and select other effective treatment methods early for cases that are not sensitive to chemotherapy to avoid delaying treatment. Studies to predict the sensitivity of tumor cells to chemotherapy by detection of molecular markers such as p53, p21, E-cadherin, Ki-67, Bcl-2, Bax, CD40 and CD40L have been reported. positive expression of p53 and p21 suggests reduced survival and does not support bladder preservation; positive expression of the pro-apoptotic tumor markers Bax and CD40L suggests improved survival Conversely, positive expression of anti-apoptotic tumor markers such as Bcl-2 can indicate poor prognosis and insensitivity to neoadjuvant chemotherapy. Randomized clinical trials suggest improved survival and prolonged survival after neoadjuvant chemotherapy with cisplatin and local radiotherapy in the Bcl-2 negative group compared to the positive group. In recent years, studies have begun to investigate the value of HER2/neu, survivin, matrix metalloproteinase 2 (MMP-2) and multi-drug resistance proteins to predict tumor sensitivity to neoadjuvant chemotherapy and conservative treatment with bladder preservation. With the advancement of technology, we have transitioned from single gene single signal channel studies to comprehensive multi-gene multi-signal channel studies, using a small amount of tissue, to detect alterations in DNA, mRNA and protein expression, and using micro-matrix microarrays to simultaneously detect the expression status of multiple gene fragments and proteins, to better understand the interactions between multiple genes and signal channels, and further understand the mechanisms of bladder cancer development. screen sensitive patients for neoadjuvant chemotherapy and which patients are suitable for conservative treatment with bladder preservation. VII. CONCLUSIONS From the present data, radical cystectomy with lymph node dissection remains the standard of care for invasive uroepithelial carcinoma of the bladder. The administration of cisplatin-based neoadjuvant chemotherapy prior to local treatment of invasive bladder uroepithelial carcinoma may improve the 5-year survival rate by at least 5%, and the improvement in survival with neoadjuvant therapy may be further improved with the advent of new regimens of new drugs such as GC, which needs to be validated by large samples of randomized clinical trials. Patients sensitive to neoadjuvant chemotherapy may be considered for conservative treatment with bladder preservation without compromising survival. Chemotherapy and radiotherapy with local conservative treatment is an alternative treatment to radical cystectomy that preserves the bladder and improves quality of life. 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