Neoadjuvant chemotherapy for muscle-infiltrating bladder tumors
Abstract: Platinum-based neoadjuvant chemotherapy reduces the stage of muscle-infiltrating bladder tumors, increases patient survival, and offers the possibility of bladder preservation, so among them, neoadjuvant chemotherapy gemcitabine combined with cisplatin regimen is gradually becoming one of the standard regimens for the treatment of muscle-infiltrating bladder tumors. This article presents a review on the application of neoadjuvant chemotherapy in muscle-invasive bladder tumors. Chen Haigo, Department of Urology, Shanghai Renji Hospital
Abstract:The neoadjuvant chemotherapy combined with cisplatin can down-stage the stage of the muscle-invasive bladder cancer, prolong the patients Neoadjuvant gemcitabine and cisplatin has become one of the standard In this review, neoadjuvant chemotherapy in the muscle-invasive bladder cancer was presented.
Keywords: neoadjuvant chemotherapy, bladder tumor
Key word: neoadjuvant chemotherapy, bladder carcinoma
Bladder tumors are the most common urological malignancies, of which muscle-invasive (T2,T3,T4a) ones account for most of them. Since the first modern radical treatment of bladder tumors was proposed by Whitman and Marshall in 1962, the incidence of bladder tumor recurrence after radical surgery remains quite high, and tumor stage and the number of invading lymph nodes are two independent risk factors affecting bladder tumor recurrence. Reducing tumor stage can help improve the prognosis of patients with bladder tumors. The main cause of tumor recurrence is the presence of micro-metastases. Therefore, adjuvant chemotherapy for the systemic system can be used to eradicate micrometastases while undergoing surgery, and preoperative neoadjuvant chemotherapy is becoming more acceptable.
I. Characteristics and advantages of neoadjuvant chemotherapy
Neoadjuvant chemotherapy given prior to local treatment can reduce the size of the primary tumor and control micro-metastases. This is particularly important in patients with muscle-infiltrating bladder tumors, as half of the patients with muscle-infiltrating bladder tumors have occult micrometastases. It is worth pointing out that before total cystectomy or radiation therapy, the patient is in a better general condition and mostly tolerates chemotherapy, which also facilitates better treatment of the tumor.
There is no evidence that the administration of neoadjuvant chemotherapy increases the risk of progression of the primary tumor. A randomized controlled trial of 976 cases by the European Organisation for Research on Cancer and Treatment and the UK Medical Research Council [1] showed only a 5.5% increase in 3-year survival and a 6.5 month increase in median survival time in the group that received 3 cycles of a combination chemotherapy regimen of cisplatin, methotrexate and vincristine compared to the group that did not receive chemotherapy. However, this trial also noted no statistical difference in the proportion of people who could not tolerate surgery due to tumor progression in both groups, whether they received neoadjuvant chemotherapy first or went directly to radical surgery.
A foreign Meta-analysis [2] noted that neoadjuvant chemotherapy had a favorable effect in patients with muscle-infiltrating bladder tumors, and this effect was most pronounced in platinum-based combination chemotherapy. Combination chemotherapy reduced the risk of death by 13% and increased the 5-year survival rate 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 total excision, radiotherapy or radiotherapy plus total excision, all of which have similar chemotherapy benefits. It was also noted that platinum alone was not supported as a chemotherapy regimen and that there was a significant difference between the two groups with platinum alone and combination chemotherapy (p=0.004).
II. Regimens of neoadjuvant chemotherapy and their efficacy
1.MVAC
Methotrexate, vincristine, and adriamycin combined with cisplatin (MVAC) regimen was first used in adjuvant chemotherapy after total cystectomy in oncology patients. A non-randomized trial demonstrated chemotherapy response rates of up to 70% in patients with metastases in a platinum-based MVAC combination chemotherapy regimen. [3] In another randomized trial, it was proposed that the MVAC four-drug combination regimen had a better response rate than cisplatin alone in patients with metastases, with a 5-year progression-free survival of 3.4%. [4] Two successive trials found higher response rates with the MVAC regimen in patients with either localized or metastatic bladder tumors, and randomized trials also confirmed that the MVAC regimen was more effective than cisplatin alone or cisplatin plus cyclophosphamide and adriamycin. [5,6] Neoadjuvant chemotherapy with MVAC allows bladder preservation and disease-free survival for up to 10 years in patients with muscle-infiltrating bladder tumors.
A controlled trial by Grossman [7] et al. clearly showed that the application of MVAC combined with chemotherapy reduced residual tumor in bladder specimens of patients with bladder tumors and improved survival associated with this, with a median survival time of up to 21 months. Such a survival benefit with MVAC neoadjuvant chemotherapy was associated with a downgrading of the tumor to pT0, compared to the total cystectomy group alone. Forty-eight cases (38%) in the neoadjuvant chemotherapy group had no tumor detected in intraoperative specimens, 26 of which were T2 at enrollment and 22 of which were T3 and T4a at enrollment; compared with only 15% in the surgical resection alone group without chemotherapy (P < 0.001), with an associated 5-year survival rate of 85%. Chemotherapy downgrading was not the only criterion guiding the selection of neoadjuvant chemotherapy, as the median survival time in the combination chemotherapy group with residual tumor in the surgically resected specimen was the same as in the surgical resection-only group with residual tumor.
Hematologic and gastrointestinal reactions occurred in 1/3 of patients in the MVAC group, but all patients eventually recovered with no treatment-related deaths. More importantly, the MVAC regimen neither compromised patients’ chances of tolerating total resection nor did it increase death or procedure-related complications. [7]
2, GC
Some studies have shown that gemcitabine is safe and effective in patients with uroepithelial tumors, and some studies have also confirmed the synergistic effect of gemcitabine on cisplatin. [8,9] Gemcitabine combined with cisplatin (GC) regimens have better tolerability, and a three-week dosing regimen has been proposed to enhance the efficacy by boosting blood levels. The use of the GC regimen also does not increase the risk of 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 grading and was similar to the MVAC regimen in terms of prolonging disease-free survival time and shrinking or eliminating residual foci. After applying a four-cycle GC regimen, 36% of 39 patients were downgraded to below pT2 and 26% to pT0; compared to 35% and 28%, respectively, for the MVAC regimen. All patients downgraded to below pT2 had a median disease-free survival time of 30 months.
In a long-term controlled trial, Von der Maase [12] et al. suggested that the GC regimen provided similar survival with better safety and tolerability compared to the MVAC regimen. In terms of chemotherapy response rate, it was 49% in the GC group and 46% in the MVAC group. the toxic mortality rate was 1% in the GC group and 3% in the MVAC group. the MVAC group had more neutropenia and consequent fever and sepsis, as well as severe mucositis and alopecia, than the GC group. Given this advantage of the GC regimen, several studies are currently underway to investigate whether the GC regimen can become the standard of care for neoadjuvant chemotherapy.
3. paclitaxel-based combined with platinum
Bimias [13] et al. proposed that the application of a 3-cycle docetaxel combined with cisplatin (TC) regimen plus cystectomy achieved a 5-year survival rate of 60.34% and a 5-year progression-free survival of 57.11%. 15 cases (30%) showed toxic reactions in the form of leukopenia, followed by anemia and constipation. Thrombosis and gastritis, which are common in the MVAC regimen, were not observed in this trial.
Paclitaxel, carboplatin and gemcitabine (PCaG) regimens have also been proposed for neoadjuvant chemotherapy, achieving chemotherapy response rates of 70.1% and 78.4% in patients at 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 proven to be chemotherapy-induced. [14] The application of paclitaxel analogs in combination with platinum as neoadjuvant chemotherapy is still immature, pending more randomized controlled trials to observe its toxic effects and whether it can definitively improve the survival of patients.
Several trials have been conducted in North America and Europe including the combination of sunitinib, dasatinib, or erlotinib in MVAC or GC regimens as neoadjuvant chemotherapy to try to achieve better survival and to screen patients sensitive to combination chemotherapy. [15] Ongoing clinical trials of these applied molecular biology drugs offer the possibility of individualized treatment of patients with bladder tumors and increased response to chemotherapy.
III. Neoadjuvant chemotherapy and preservation of the bladder
Some patients with chemotherapy-sensitive tumors who achieve 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 with the application of radiotherapy or aggressive TURBt after neoadjuvant chemotherapy. [16]
Sternberg [17] et al. performed 3 cycles of MVAC neoadjuvant chemotherapy followed by TURBt only in 104 patients with T2 to T4 bladder tumors for 52 patients, of whom the tumor stage was reduced to T049 with a mean follow-up of 56 months, 31 (60%) were alive and 23 (44%) had an intact bladder. 18 (35%) of the 52 patients who underwent TURBt ) had no recurrence or progression. The 5-year survival rate was 69.0% for patients who were pathologically confirmed to be fully effective to neoadjuvant chemotherapy with postoperative rechemotherapy, compared to 26% for those who remained invasive after neoadjuvant chemotherapy. This study demonstrates the ability to offer bladder-preserving treatment to patients who respond to neoadjuvant chemotherapy.
Herr [18] et al. study of 111 cases undergoing neoadjuvant chemotherapy with the MVAC regimen found 60 (54%) achieved a complete response T0, of which 28 received TURBt only, 15 partial resections and 17 total resections. 6 cases eventually died, including 4 (9%) due to neoplasia. 24 (56%) had tumor recurrence between 5 and 96 months, 13 infiltrative (30%) and superficial in 11 cases (26%). 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 neoplasia. Therefore, patients who choose to preserve their bladder after neoadjuvant chemotherapy must undergo more frequent evaluation and multiple invasive tests to rule out recurrence and, if necessary, surgical removal of the bladder.
A retrospective study reported survival outcomes in 63 patients who received neoadjuvant chemotherapy with GC regimens and ultimately declined cystectomy; all patients were followed for more than 5 years, with a median follow-up of 86 months. 40 (64%) survived, of whom 54% had an intact functional bladder; 19 (30%) had an infiltrative recurrence. Selection of patients with bladder tumors that responded to chemotherapy was the basis for the implementation of bladder preservation. Single tumors (P < 0.001), tumors < 5 cm (P = 0.01), and especially those where TURBt at re-grading allowed complete resection of the infiltrating muscular layer (P = 0.02) were associated with a significantly better prognosis [23]. In addition, a multicenter phase III clinical trial by Sternberg [17] 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 bladder preservation was 67%, with a median survival time of 109 months; 47% retained an intact bladder. Among older patients, this was also in line with the overall trend that the 5-year survival rate was much higher in patients who were effective to chemotherapy than in those who were not (68% versus 37%). Old age (≥70 years) is not an absolute contraindication to bladder preservation.
Of note, in the study by Sternberg [17] of 13 patients who underwent partial cystectomy, two had superficial tumor recurrence and three had progressive tumor recurrence. The median follow-up in this group was up to 88 months, with a 5-year survival of 69%; 2 cases died at years 8 and 12 for other reasons, retaining an intact bladder at the time of death. 4 cases survived with a normally functioning bladder.
Preservation of the bladder after neoadjuvant chemotherapy has the advantage of reducing surgery, eliminating the need for urinary diversion and preserving sexual function, and improving quality of life, but some studies have also shown that preservation of the bladder has similar survival rates to both compared to radical resection. [20,21] Although the latest edition of the National Cancer Network (NCCN) guidelines for the treatment of bladder tumors states that bladder preservation may be an option in patients with T2 and T3 in combination with chemotherapy in the absence of leukopenia, this treatment option still requires a large sample size of prospective randomized controlled trials to compare survival with the choice of bladder preservation or radical resection after neoadjuvant chemotherapy. Also, more evidence is needed to show that partial cystectomy is a bladder preservation option to consider.
Current platinum-based neoadjuvant chemotherapy reduces tumor grade, improves survival, and allows for the option of bladder preservation with close testing in a subset of patients who have a complete response to neoadjuvant chemotherapy; however, the 5% improvement in 5-year overall survival is still limited, and better combination regimens or drugs and reliance on specific tumor markers for truly individualized treatment are needed. The ongoing large-scale research and study of the use of molecular biology drugs in combination with traditional platinum-based chemotherapy regimens 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-infiltrating bladder tumors.
Bladder tumors are the most common urologic malignancies, with muscle-infiltrating (T2,T3,T4a) ones accounting for the majority of them. Since the first modern radical treatment of bladder tumors was proposed by Whitman and Marshall in 1962, the incidence of bladder tumor recurrence after radical surgery remains quite high, and tumor stage and the number of invading lymph nodes are two independent risk factors affecting bladder tumor recurrence. Reducing tumor stage can help improve the prognosis of patients with bladder tumors. The main cause of tumor recurrence is the presence of micro-metastases. Therefore, adjuvant chemotherapy for the systemic system can be used to eradicate micrometastases while undergoing surgery, and preoperative neoadjuvant chemotherapy is becoming more acceptable.
I. Characteristics and advantages of neoadjuvant chemotherapy
Neoadjuvant chemotherapy given prior to local treatment can reduce the size of the primary tumor and control micro-metastases. This is particularly important in patients with muscle-infiltrating bladder tumors, as half of the patients with muscle-infiltrating bladder tumors have occult micrometastases. It is worth pointing out that before total cystectomy or radiation therapy, the patient is in a better general condition and mostly tolerates chemotherapy, which also facilitates better treatment of the tumor.
There is no evidence that the administration of neoadjuvant chemotherapy increases the risk of progression of the primary tumor. A randomized controlled trial of 976 cases by the European Organisation for Research on Cancer and Treatment and the UK Medical Research Council [1] showed only a 5.5% increase in 3-year survival and a 6.5 month increase in median survival time in the group that received 3 cycles of a combination chemotherapy regimen of cisplatin, methotrexate and vincristine compared to the group that did not receive chemotherapy. However, this trial also noted no statistical difference in the proportion of people who could not tolerate surgery due to tumor progression in both groups, whether they received neoadjuvant chemotherapy first or went directly to radical surgery.
A foreign Meta-analysis [2] noted that neoadjuvant chemotherapy had a favorable effect in patients with muscle-infiltrating bladder tumors, and this effect was most pronounced in platinum-based combination chemotherapy. Combination chemotherapy reduced the risk of death by 13% and increased the 5-year survival rate 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 total excision, radiotherapy or radiotherapy plus total excision, all of which have similar chemotherapy benefits. It was also noted that platinum alone was not supported as a chemotherapy regimen and that there was a significant difference between the two groups with platinum alone and combination chemotherapy (p=0.004).
II. Regimens of neoadjuvant chemotherapy and their efficacy
1.MVAC
Methotrexate, vincristine, and adriamycin combined with cisplatin (MVAC) regimen was first used in adjuvant chemotherapy after total cystectomy in oncology patients. A non-randomized trial demonstrated chemotherapy response rates of up to 70% in patients with metastases in a platinum-based MVAC combination chemotherapy regimen. [3] In another randomized trial, it was proposed that the MVAC four-drug combination regimen had a better response rate than cisplatin alone in patients with metastases, with a 5-year progression-free survival of 3.4%. [4] Two successive trials found higher response rates with the MVAC regimen in patients with either localized or metastatic bladder tumors, and randomized trials also confirmed that the MVAC regimen was more effective than cisplatin alone or cisplatin plus cyclophosphamide and adriamycin. [5,6] Neoadjuvant chemotherapy with MVAC allows bladder preservation and disease-free survival for up to 10 years in patients with muscle-infiltrating bladder tumors.
A controlled trial by Grossman [7] et al. clearly showed that the application of MVAC combined with chemotherapy reduced residual tumor in bladder specimens of patients with bladder tumors and improved survival associated with this, with a median survival time of up to 21 months. Such a survival benefit with MVAC neoadjuvant chemotherapy was associated with a downgrading of the tumor to pT0, compared to the total cystectomy group alone. Forty-eight cases (38%) in the neoadjuvant chemotherapy group had no tumor detected in intraoperative specimens, 26 of which were T2 at enrollment and 22 of which were T3 and T4a at enrollment; compared with only 15% in the surgical resection alone group without chemotherapy (P < 0.001), with an associated 5-year survival rate of 85%. Chemotherapy downgrading was not the only criterion guiding the selection of neoadjuvant chemotherapy, as the median survival time in the combination chemotherapy group with residual tumor in the surgically resected specimen was the same as in the surgical resection-only group with residual tumor.
Hematologic and gastrointestinal reactions occurred in 1/3 of patients in the MVAC group, but all patients eventually recovered with no treatment-related deaths. More importantly, the MVAC regimen neither compromised patients’ chances of tolerating total resection nor did it increase death or procedure-related complications. [7]
2, GC
Some studies have shown that gemcitabine is safe and effective in patients with uroepithelial tumors, and some studies have also confirmed the synergistic effect of gemcitabine on cisplatin. [8,9] Gemcitabine combined with cisplatin (GC) regimens have better tolerability, and a three-week dosing regimen has been proposed to enhance the efficacy by boosting blood levels. The use of the GC regimen also does not increase the risk of 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 grading and was similar to the MVAC regimen in terms of prolonging disease-free survival time and shrinking or eliminating residual foci. After applying a four-cycle GC regimen, 36% of 39 patients were downgraded to below pT2 and 26% to pT0; compared to 35% and 28%, respectively, for the MVAC regimen. All patients downgraded to below pT2 had a median disease-free survival time of 30 months.
In a long-term controlled trial, Von der Maase [12] et al. suggested that the GC regimen provided similar survival with better safety and tolerability compared to the MVAC regimen. In terms of chemotherapy response rate, it was 49% in the GC group and 46% in the MVAC group. the toxic mortality rate was 1% in the GC group and 3% in the MVAC group. the MVAC group had more neutropenia and consequent fever and sepsis, as well as severe mucositis and alopecia, than the GC group. Given this advantage of the GC regimen, several studies are currently underway to investigate whether the GC regimen can become the standard of care for neoadjuvant chemotherapy.
3. paclitaxel-based combined with platinum
Bimias [13] et al. proposed that the application of a 3-cycle docetaxel combined with cisplatin (TC) regimen plus cystectomy achieved a 5-year survival rate of 60.34% and a 5-year progression-free survival of 57.11%. 15 cases (30%) showed toxic reactions in the form of leukopenia, followed by anemia and constipation. Thrombosis and gastritis, which are common in the MVAC regimen, were not observed in this trial.
Paclitaxel, carboplatin and gemcitabine (PCaG) regimens have also been proposed for neoadjuvant chemotherapy, achieving chemotherapy response rates of 70.1% and 78.4% in patients at 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 proven to be chemotherapy-induced. [14] The application of paclitaxel analogs in combination with platinum as neoadjuvant chemotherapy is still immature, pending more randomized controlled trials to observe its toxic effects and whether it can definitively improve the survival of patients.
Several trials have been conducted in North America and Europe including the combination of sunitinib, dasatinib, or erlotinib in MVAC or GC regimens as neoadjuvant chemotherapy to try to achieve better survival and to screen patients sensitive to combination chemotherapy. [15] Ongoing clinical trials of these applied molecular biology drugs offer the possibility of individualized treatment of patients with bladder tumors and increased response to chemotherapy.
III. Neoadjuvant chemotherapy and preservation of the bladder
Some patients with chemotherapy-sensitive tumors who achieve 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 with the application of radiotherapy or aggressive TURBt after neoadjuvant chemotherapy. [16]
Sternberg [17] et al. performed 3 cycles of MVAC neoadjuvant chemotherapy followed by TURBt only in 104 patients with T2 to T4 bladder tumors for 52 patients, of whom the tumor stage was reduced to T049 with a mean follow-up of 56 months, 31 (60%) were alive and 23 (44%) had an intact bladder. 18 (35%) of the 52 patients who underwent TURBt ) had no recurrence or progression. The 5-year survival rate was 69.0% for patients who were pathologically confirmed to be fully effective to neoadjuvant chemotherapy with postoperative rechemotherapy, compared to 26% for those who remained invasive after neoadjuvant chemotherapy. This study demonstrates the ability to offer bladder-preserving treatment to patients who respond to neoadjuvant chemotherapy.
Herr [18] et al. study of 111 cases undergoing neoadjuvant chemotherapy with the MVAC regimen found 60 (54%) achieved a complete response T0, of which 28 received TURBt only, 15 partial resections and 17 total resections. 6 cases eventually died, including 4 (9%) due to neoplasia. 24 (56%) had tumor recurrence between 5 and 96 months, 13 infiltrative (30%) and superficial in 11 cases (26%). 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 neoplasia. Therefore, patients who choose to preserve their bladder after neoadjuvant chemotherapy must undergo more frequent evaluation and multiple invasive tests to rule out recurrence and, if necessary, surgical removal of the bladder.
A retrospective study reported survival outcomes in 63 patients who received neoadjuvant chemotherapy with GC regimens and ultimately declined cystectomy; all patients were followed for more than 5 years, with a median follow-up of 86 months. 40 (64%) survived, of whom 54% had an intact functional bladder; 19 (30%) had an infiltrative recurrence. Selection of patients with bladder tumors that responded to chemotherapy was the basis for the implementation of bladder preservation. Single tumors (P < 0.001), tumors < 5 cm (P = 0.01), and especially those where TURBt at re-grading allowed complete resection of the infiltrating muscular layer (P = 0.02) were associated with a significantly better prognosis [23]. In addition, a multicenter phase III clinical trial by Sternberg [17] 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 bladder preservation was 67%, with a median survival time of 109 months; 47% retained an intact bladder. Among older patients, this was also in line with the overall trend that the 5-year survival rate was much higher in patients who were effective to chemotherapy than in those who were not (68% versus 37%). Old age (≥70 years) is not an absolute contraindication to bladder preservation.
Of note, in the study by Sternberg [17] of 13 patients who underwent partial cystectomy, two had superficial tumor recurrence and three had progressive tumor recurrence. The median follow-up in this group was up to 88 months, with a 5-year survival of 69%; 2 cases died at years 8 and 12 for other reasons, retaining an intact bladder at the time of death. 4 cases survived with a normally functioning bladder.
Preservation of the bladder after neoadjuvant chemotherapy has the advantage of reducing surgery, eliminating the need for urinary diversion and preserving sexual function, and improving quality of life, but some studies have also shown that preservation of the bladder has similar survival rates to both compared to radical resection. [20,21] Although the latest edition of the National Cancer Network (NCCN) guidelines for the treatment of bladder tumors states that bladder preservation may be an option in patients with T2 and T3 in combination with chemotherapy in the absence of leukopenia, this treatment option still requires a large sample size of prospective randomized controlled trials to compare survival with the choice of bladder preservation or radical resection after neoadjuvant chemotherapy. Also, more evidence is needed to show that partial cystectomy is a bladder preservation option to consider.
Current platinum-based neoadjuvant chemotherapy reduces tumor grade, improves survival, and allows for the option of bladder preservation with close testing in a subset of patients who have a complete response to neoadjuvant chemotherapy; however, the 5% improvement in 5-year overall survival is still limited, and better combination regimens or drugs and reliance on specific tumor markers for truly individualized treatment are needed. The ongoing large-scale research and study of the use of molecular biology drugs in combination with traditional platinum-based chemotherapy regimens 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-infiltrating bladder tumors.
Reference.
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