Abstract:Platinum-based neoadjuvant chemotherapy can down-stage the stage of muscle-invasive bladder tumors, increase patient survival, and provide patients with the possibility of preserving the bladder, so one of the neoadjuvant chemotherapy gemcitabine combined with cisplatin regimen has gradually become one of the standard regimens for the treatment of muscle-invasive bladder tumors. This article provides a review on the application of neoadjuvant chemotherapy in muscle-invasive bladder tumors.Abstract:The neoadjuvant chemotherapy combined cisplatin can down-stage the stage of the muscle-invasive bladder cancer, prolong the patients’ survivals and have the opportunity for preserving the bladder. Neoadjuvant gemcitabine and cisplatin has become one of the standard therapies. Neoadjuvant gemcitabine and cisplatin has become one of the standard therapies for muscle-invasive bladder cancer. In this review, neoadjuvant chemotherapy in the muscle-invasive bladder cancer was presented. cancer was presented.Cao Ming, Department of Urology, Shanghai Renji HospitalKey word: neoadjuvant chemotherapy, bladder tumorKey word: neoadjuvant chemotherapy, bladder carcinomaBladder tumors are the most common urological malignant tumors, of which muscle-invasive (T2,T3,T4a) ones account for the most of them. Since Whitman and Marshall first proposed modern radical surgery for bladder tumors in 1962, the chance of recurrence of bladder tumors after radical surgery is still quite high, and the stage of the tumor and the number of lymph nodes invaded are two independent risk factors affecting the recurrence of bladder tumors. Reducing the tumor stage, on the other hand, can help improve the prognosis of patients with bladder tumors. The main cause of tumor recurrence is the presence of microscopic metastases. Therefore, adjuvant chemotherapy for systemic system can be used to eliminate micrometastases while undergoing surgery, and neoadjuvant chemotherapy in the preoperative period is gradually accepted. I. Characteristics and advantages of neoadjuvant chemotherapy before local treatment can reduce the size of the primary tumor and control small metastases. This is especially important for patients with muscle-invasive bladder tumors, because half of the patients with muscle-invasive bladder tumors have hidden micrometastases. It is worth pointing out that prior to total cystectomy or radiation therapy, patients are in relatively good general condition and tend to tolerate chemotherapy, which also facilitates better treatment of the tumor. There is no evidence that giving neoadjuvant chemotherapy increases the risk of progression of the primary tumor. A randomized controlled trial of 976 cases by the European Organization for Research in Cancer and Therapy and the UK Medical Research Council [1] showed that a 3-cycle chemotherapy regimen combining cisplatin, methotrexate, and vincristine improved 3-year survival by only 5.5% and median survival time by only 6.5 months compared with the group that did not receive chemotherapy. However, this trial also pointed out that whether the group received neoadjuvant chemotherapy first or the group received radical surgery directly, the proportion of the number of people who could not withstand surgery due to tumor progression was similar in the two groups and was not statistically different. A foreign Meta-analysis [2] noted that neoadjuvant chemotherapy has a favorable effect on patients with muscle-invasive bladder tumors, and this effect is most pronounced in platinum-based combination chemotherapy. Combination chemotherapy reduced the risk of death by 13% and increased 5-year survival by 5% (P=0.016). Combination chemotherapy can be beneficial for disease-free survival, local tumor-free survival, and metastasis-free survival. The effect of combination chemotherapy can be independent of the local treatment approach, whether it is total resection, radiotherapy, or radiotherapy plus total resection, all of which have similar chemotherapy benefits. It was also noted that platinum alone was not supported as a chemotherapy regimen, and there was a significant difference between the two groups of platinum alone and combination chemotherapy (P=0.004). Second, neoadjuvant chemotherapy regimens and their efficacy 1, MVAC methotrexate, vincristine, adriamycin combined with cisplatin (MVAC) regimen was firstly used in adjuvant chemotherapy after total cystectomy in tumor patients. In a non-randomized trial it was shown that in platinum-based MVAC combination chemotherapy regimens in patients with metastases, the response rate to chemotherapy was as high as 70%. [3] In another randomized trial it was suggested that the four-agent MVAC combination regimen had a better response rate than cisplatin alone in patients with metastatic tumors, with a 5-year progression-free survival of 3.4%. [4] Two consecutive trials have found that the MVAC regimen has a high response rate in patients with both localized and metastatic bladder tumors, and randomized trials have confirmed that the MVAC regimen is more effective than cisplatin alone or cisplatin plus cyclophosphamide and adriamycin. [5,6] Neoadjuvant chemotherapy with MVAC allows patients with muscle-invasive bladder tumors to have bladder preservation and disease-free survival for up to a decade, and a controlled trial by Grossman [7] et al. clearly demonstrated that the use of MVAC in combination with chemotherapy reduces residual tumors in bladder specimens from patients with bladder tumors and improves the associated survival, with an increase in the median survival time of up to 21 months. Compared with the total cystectomy group alone, the MVAC neoadjuvant chemotherapy followed by total cystectomy group reduced the risk of death by 33%. such a survival benefit from MVAC neoadjuvant chemotherapy was associated with downgrading the tumor to pT0. In the neoadjuvant chemotherapy group, there were 48 cases (38%) in which no tumor was detected in the intraoperative specimen, 26 of which were T2 at entry and 22 of which were T3 and T4a at entry; this compares with only 15% in the surgical resection alone without chemotherapy group (P < 0.001), with an associated 5-year survival rate of 85%. Chemo downstaging was not the only criterion guiding the choice of neoadjuvant chemotherapy, as the median survival time for those with residual tumors in surgically resected specimens in the combination chemotherapy group was the same as for those with residual tumors in the surgical resection-only group.Hematologic and gastrointestinal reactions were noted in 1/3 of the patients in the MVAC group, but all patients ultimately recovered and had no treatment-related deaths. More importantly, the MVAC regimen neither compromised patients' chances of tolerating total resection nor increased death or surgery-related complications. [7] 2. GC There are studies showing that gemcitabine is safe and effective in patients with uroepithelial tumors, as well as studies confirming the synergistic effect of gemcitabine on cisplatin. [8,9] Gemcitabine combined with cisplatin (GC) regimen has better tolerability, and some scholars have proposed the use of three-week dosing method to enhance the blood concentration and enhance the efficacy. The use of the GC regimen also does not increase inoperable disease progression due to 12 weeks of chemotherapy. [10] A retrospective study by Dash [11] et al. showed that the use of a GC regimen reduced tumor grade and was similar to the MVAC regimen in terms of prolonging disease-free survival and shrinking or eliminating residual foci. After applying four cycles of the GC regimen, 36% of 39 patients were downgraded to less than pT2 and 26% to pT0; compared to 35% and 28%, respectively, with the MVAC regimen. All patients who downgraded to less than pT2 achieved a disease-free median survival time of 30 months.Von der Maase [12] et al. suggested in a long-term controlled trial that the GC regimen provided similar survival with better safety and tolerability compared to the MVAC regimen. The response rate to chemotherapy was 49% in the GC group and 46% in the MVAC group.Toxicity mortality was 1% in the GC group and 3% in the MVAC group.There was more neutropenia and consequently fever and sepsis, as well as severe mucositis and alopecia in the MVAC group compared to the GC group. In view of this advantage of the GC regimen, several ongoing studies are aimed at investigating whether the GC regimen can become the standard regimen for neoadjuvant chemotherapy.3. Paclitaxel-based combined with platinum Bimias [13] et al. suggested that the application of a 3-cycle docetaxel-combined cisplatin (TC) regimen plus cystectomy resulted in a 5-year survival of 60.34% and 5-year progression-free survival of 57.11%.15 The GC regimen has been shown to be effective in the management of neoadjuvant chemotherapy, but it is not recommended for the management of neoadjuvant chemotherapy. cases (30%) experienced toxic reactions of leukopenia followed by anemia and constipation. Thrombosis and gastritis, which are common in MVAC regimens, were not observed in this trial. Paclitaxel, carboplatin and gemcitabine (PCaG) regimens have also been proposed for neoadjuvant chemotherapy, with achievable chemotherapy response rates of 70.1% and 78.4% in patients with T2T3 and T4, respectively. However, a total of 79% of patients developed hematologic toxicity; seven deaths occurred after chemotherapy and radical resection, and one case was shown to be chemotherapy-induced. [14] The use of paclitaxel analogs in combination with platinum as neoadjuvant chemotherapy is still immature, and more randomized controlled trials are needed to observe its toxicity response and whether it can definitely improve the survival of patients. Several trials have been conducted in North America and Europe, including combining sunitinib, dasatinib, or erlotinib with MVAC or GC regimens as neoadjuvant chemotherapy to try to achieve better survival and to screen patients sensitive to the combination.[15] Ongoing trials are underway to determine whether the combination of paclitaxel with platinum is effective in improving survival. [15] These ongoing clinical trials applying molecular biology drugs offer the possibility of individualizing the treatment of patients with bladder tumors and increasing the response to chemotherapy. Third, neoadjuvant chemotherapy and preservation of the bladder Some patients with chemotherapy-sensitive tumors who get a complete response after neoadjuvant chemotherapy, or even preserve their bladder, are certainly options worth considering for patients and clinicians. In contrast to other tumors, bladder tumors may have the option of bladder preservation after neoadjuvant chemotherapy with the application of radiotherapy or aggressive TURBt. [16] Sternberg [17] et al. performed 3 cycles of neoadjuvant chemotherapy with MVAC in 104 patients with T2 to T4 bladder tumors, followed by TURBt only for 52 patients, of which the tumor stage was downgraded to T049, with a mean follow-up of 56 months, 31 (60%) were alive, and 23 (44%) had an intact bladder.18 out of 52 patients who underwent TURBt (35%) had no recurrence or progression. Pathologically confirmed patients who were fully effective on neoadjuvant chemotherapy and who were re-treated with chemotherapy after surgery had a 5-year survival rate of 69.0%, compared with 26% for those who remained invasive after neoadjuvant chemotherapy. This study demonstrated the ability to offer bladder preservation therapy to patients who responded to neoadjuvant chemotherapy.Herr [18] et al. study of 111 patients who underwent neoadjuvant chemotherapy with the MVAC regimen found that 60 (54%) achieved a complete response T0, of which 28 underwent TURBt only, 15 had partial resections, and 17 had total resections.6 ultimately died, which included 4 ( 9%) were due to new tumors. 24 (56%) had tumor recurrence between 5 and 96 months, 13 (30%) invasive and 11 (26%) superficial. Most of those who reached T0 after neoadjuvant chemotherapy with MVAC were able to retain their bladder for up to 10 years after chemotherapy, but were still at risk of neoplastic development. Therefore, patients who choose to retain their bladder after neoadjuvant chemotherapy must undergo more frequent evaluations and multiple invasive procedures to rule out recurrence and, if necessary, surgical removal of the bladder. A retrospective study reported survival outcomes in 63 patients who ultimately declined cystectomy after neoadjuvant chemotherapy with a GC regimen. all patients were followed for more than 5 years, with a median follow-up of 86 months. 40 (64%) survived, of whom 54% had intact, functional bladders; 19 (30%) had invasive recurrences. Selection of patients with bladder tumors that respond to chemotherapy is the basis for practicing bladder preservation. A significantly more favorable prognosis is achieved with single tumors (P < 0.001), tumors < 5 cm (P = 0.01), and especially tumors in which TURBt can completely resect the infiltrating muscularis propria at the time of re-grading (P = 0.02) [23]. In addition, Sternberg's [17] multicenter phase III clinical trial showed a median survival time of 90 months (7.5 years) in 27 elderly (≥70 years) patients; of these, the 5-year survival rate with preservation of the bladder was 67%, with a median survival time of 109 months; and 47% retained an intact bladder. In older patients, and in line with the overall trend, the 5-year survival rate was much higher in patients who were effective on chemotherapy than in those who were not (68% versus 37%). Old age (≥70 years) is not an absolute contraindication to bladder preservation. Of note, of the 13 patients who underwent partial cystectomy in the study by Sternberg [17], two had superficial tumor recurrence and three had progressive tumor recurrence. The median follow-up in this group was as high as 88 months, with a 5-year survival of 69%; 2 died of other causes at years 8 and 12 with intact bladders at the time of death. 4 remained alive with normal functioning bladders. Preservation of the bladder after neoadjuvant chemotherapy has the advantage of reducing the number of surgeries, eliminating the need for urinary diversion and preserving sexual function, and improving quality of life, but it has also been shown that preservation of the bladder compared to radical resection has similar survival rates for both. [20,21] Although the latest edition of the National Cancer Network (NCCN) guidelines for the treatment of bladder tumors states that bladder preservation can be combined with the option of chemotherapy in patients with T2 and T3 if there is no leukopenia, large sample sizes of prospective, randomized, controlled trials comparing survival with the option of bladder preservation or radical resection after neoadjuvant chemotherapy are still needed for this treatment option. Also, more evidence is needed to show that partial cystectomy is a bladder-preserving option to consider. Currently, platinum-based neoadjuvant chemotherapy can reduce tumor grade and improve survival, and bladder preservation may be an option for a subset of patients who have a complete response to neoadjuvant chemotherapy under close scrutiny; however, the improvement in overall 5-year survival of 5% is still limited, and there is a need for better combinations of regimens or agents as well as reliance on specific tumor markers to allow for true individualization of therapy. The current large-scale development and investigation of chemotherapy regimens using molecular biology agents in combination with conventional platinum may provide a strong rationale for future individualized therapy. For most patients, neoadjuvant chemotherapy with total cystectomy and pelvic lymph node dissection is now the standard of care for muscle-invasive bladder tumors. References:[1] International collaboration of trialists on behalf of the Medical Research Council Advanced Bladder Cancer Working Party. 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