Professor Zhuowei Liu: Perioperative treatment and research progress of muscular invasive bladder cancer

20%～30% of bladder cancer is muscular invasive bladder cancer (MIBC) at first diagnosis
.

Perioperative chemotherapy, especially preoperative neoadjuvant chemotherapy, can improve the overall survival (OS) of patients with muscle invasive bladder cancer and has become one of the standard treatment options
.

In recent years, with the rise of immunotherapy, in order to further improve the survival of patients, researchers have carried out a number of studies to further optimize the perioperative treatment plan (neo-adjuvant therapy and adjuvant therapy) for patients with bladder cancer
.

The Symposium on Urology and Oncology of Guangdong Medical Association was held in Guangzhou on November 6
.

During the meeting, Professor Liu Zhuowei from Sun Yat-sen University Cancer Hospital introduced the perioperative research progress and treatment plan of muscular invasive bladder cancer in recent years
.

Neoadjuvant therapy for bladder cancer For bladder cancer, the current neoadjuvant therapy has a definite effect and has been recommended by international guidelines.
However, in the real world, there are still problems such as accurate clinical staging, persistence of efficacy, and how to select patients
.

Table neoadjuvant chemotherapy related clinical studies.
Past studies have shown that neoadjuvant cisplatin-containing chemotherapy can increase the 10-year survival rate by 6%
.

However, related clinical studies still have some limitations, which objectively affect the evaluation of the efficacy of neoadjuvant chemotherapy
.

01 Patients with pathological decline after radical neoadjuvant chemotherapy have better curative effect.
The estimated 5-year OS rate of patients who achieve complete pathological remission (pCR) and decline to ≤pT1 after neoadjuvant chemotherapy is 85%, and no pathological decline is found The 5-year OS rate of the patients is only 30-40%
.

02 Neoadjuvant chemotherapy in the treatment of elderly patients with myometrial invasive bladder cancer A study showed that neoadjuvant therapy is related to pelvic lymph node dissection (OR=4.
55, P＜0.
001)
.

Among patients ≥70 years of age who underwent radical cystectomy (RC), neoadjuvant treatment and shorter hospital stay (8.
5 vs 9.
6 days, P＜0.
001), and a reduction in rehospitalization within 30 days (8.
6% vs 10.
6%, P= 0.
003), 30-day and 90-day mortality rates were lower (1.
9% vs 3.
6%, respectively, P=0.
01 and 4.
9% vs 7.
7%, P=0.
004), and the best overall survival rate (43.
8% vs 37.
5%, P< 0.
001) Related
.

Although the use of neoadjuvant chemotherapy is low in patients ≥70 years of age, it has nothing to do with poor perioperative outcomes or mortality in elderly patients
.

For suitable elderly patients, neoadjuvant therapy can still be considered
.

03 Summary of Neoadjuvant Chemotherapy Based on Level I evidence, cisplatin-based neoadjuvant chemotherapy for bladder cancer is considered to be the standard treatment for cT2-4aN0M0 myometrial invasive bladder cancer; the survival benefit related to neoadjuvant chemotherapy for bladder cancer is mainly related to pCR It is related to disease downgrading to <pT2N0; neoadjuvant chemotherapy for bladder cancer will not affect bladder cancer resection, nor will it increase surgery-related complications; neoadjuvant chemotherapy is not recommended for patients with cisplatin intolerance, and direct surgery is recommended
.

04 Neoadjuvant regimens are added to immunotherapy.
At present, some studies have shown that immunotherapy regimens have achieved good results when used in neoadjuvant treatment for patients with cisplatin intolerance
.

Table neoadjuvant immunotherapy related research progress.
Neoadjuvant chemotherapy is added to immunotherapy.
Neoadjuvant cisplatin chemotherapy needs to further improve the pathological downgrading rate of patients with cisplatin tolerance.
After neoadjuvant chemotherapy, nearly half of the patients still have pathological stage ≥pT2.
This part of patients The prognosis is poor, can adding immunotherapy improve the efficacy? The results of the ABACUS study were announced at the ASCO conference this year.
The study included T2-T4aN0M0 and cisplatin-tolerant patients who received atilizumab (1200 mg) treatment, and two weeks later, the GC regimen (gemcitabine + cisplatin) combined with ati Lilibizumab was administered for 4 cycles, followed by RC surgery.
The primary endpoint was pathological downgrade rate (down to <pT2N0), and the secondary endpoints were pCR rate, disease recurrence-free survival (RFS), and safety
.

The results showed that a total of 44 patients were enrolled, of which 39 were evaluable patients.
Patients with cT2N0, cT3N0, and cT4N0 stages accounted for 79%, 18%, and 3%, respectively
.

The pathological downgrading rate of atilizumab combined with neoadjuvant GC regimen was 69% (27/39), reaching the primary endpoint (<pT2N0), of which 17 patients (44%) were downgraded to pT0N0
.

And the efficacy has nothing to do with PD-L1 expression
.

Neoadjuvant dual immune combination therapy A multi-center, single-arm phase II study included patients with high-risk myometrial invasive bladder cancer (cT2-T4a) who are not suitable for neoadjuvant chemotherapy containing cisplatin, aiming to evaluate duvalizumab + tremelimumab treatment Efficacy and safety of patients with cisplatin intolerance
.

The results showed that 34 patients were enrolled in the study, and 24 patients completed bladder cancer resection
.

Of the 24 patients, 12 (50%) patients were downgraded to <pT1N0, of which 10 patients (42%) achieved pathological complete remission (pCR), and 2 patients (8%) were pathologically downgraded to pT1
.

The NABUCCO study is a single-arm, open-label Phase Ib study to evaluate the efficacy and safety of neoadjuvant nivolumab + ipilimumab in patients with locally advanced urothelial cancer
.

The primary endpoint was the feasibility of surgery within 12 weeks, and the secondary endpoint was efficacy and safety
.

The results showed that the pCR rate reached 46%
.

A total of 24 patients were enrolled, 23 patients (96%) received surgery within 12 weeks, and 1 patient was delayed by 4 weeks due to immunotherapy-related adverse events
.

75% of patients received all 3 cycles of treatment (that is, the treatment plan is safe and feasible)
.

A phase Ib study explored the feasibility of nivolumab ± ipilimumab as a neoadjuvant treatment for patients with cisplatin intolerant muscle infiltrating bladder cancer
.

Looking forward to follow-up research results
.

It shows the progress of neoadjuvant immunotherapy.
In general, compared with chemotherapy/immunotherapy alone, the pCR rate of immune combined chemotherapy is comparable to or better than chemotherapy
.

At present, clinicians are most concerned about whether the pCR rate can be converted into survival time? More research on immune combination therapy is underway, and we look forward to better research results
.

05Exploration of perioperative treatment options The KEYNOTE-866 study explored the efficacy of preoperative GC + pembrolizumab neoadjuvant therapy + postoperative pembrolizumab adjuvant therapy for patients with cisplatin-resistant muscle invasive bladder cancer
.

The KEYNOTE-905 study explored the efficacy of preoperative neoadjuvant pembrolizumab + postoperative pembrolizumab adjuvant therapy for patients with cisplatin intolerance
.

New EV drugs and immune agonists are currently being explored
.

The KEYNOTE-905/EV-303 study explored pembrolizumab + bladder cancer resection vs.
pembrolizumab + EV + bladder cancer resection vs.
bladder cancer resection only for cisplatin-intolerant myometrial invasive bladder Efficacy and safety of cancer patients
.

In the previous PROPEL study, the immune agonist NKTR combined with nivolumab was used to treat 10 patients with cisplatin intolerant metastatic urothelial carcinoma, and the ORR reached 60%
.

06 Summary Based on Level I evidence, cisplatin-based neoadjuvant therapy is considered to be the standard treatment for cT2-4aN0M0 muscle invasive bladder cancer, with a 10-year benefit rate of approximately 10%
.

Existing preliminary studies have shown that the pCR of neoadjuvant immunotherapy is 29% to 60%, and the response rate of PD-L1 positive patients is higher
.

The response rate of immune combined chemotherapy is higher than that of single immunotherapy, and the response rate of dual immunotherapy is higher than that of single immunotherapy
.

The response rate of immune neoadjuvant therapy is equivalent to that of neoadjuvant chemotherapy
.

Neoadjuvant immunotherapy will not affect bladder cancer resection and is highly safe
.

Long-term survival data are not available, and neoadjuvant immunotherapy may be a new hope for patients with bladder cancer
.

The EORTC30994 study on adjuvant treatment of bladder cancer is the largest prospective, multi-center, randomized controlled clinical study to date, which explored the efficacy of immediate postoperative chemotherapy versus post-recurrence chemotherapy for pT3-pT4 patients
.

Current data show that immediate postoperative chemotherapy can bring progress-free survival (PFS) benefits, but OS has no benefit
.

Another observational study showed that a large-scale observational study from 2003 to 2006 compared the efficacy of postoperative adjuvant single-drug and observational group alone
.

The study included 5653 patients with bladder cancer with pathological T3-4 and/or lymph node positive, and 23% of the patients received adjuvant chemotherapy
.

The results showed that the 5-year OS rate of adjuvant chemotherapy patients was 37%, and that of the observation group was 29.
1% (HR=0.
7)
.

The phase III IMvigor010 study explored the efficacy of atilizumab in the adjuvant treatment of high-risk myometrial invasive urothelial carcinoma.
The study included both ypT2-T4a or ypN+ who received neoadjuvant therapy and pT3- without neoadjuvant therapy.
In T4a or pN+ patients, the primary endpoint is median disease-free survival (DFS).
The results showed that atelizumab did not improve DFS and OS in patients with ITT
.

This study is the first phase III clinical study to evaluate neoadjuvant therapy with immune checkpoint inhibitors in patients with muscular invasive bladder cancer.
Atelizumab has no new safety issues
.

In the future, we can further explore its efficacy in the benefitable subgroup
.

The Phase III CheckMate 274 study explored the efficacy of nivolumab adjuvant therapy for high-risk muscular invasive urothelial carcinoma
.

The study included 709 patients with high-risk muscular invasive urothelial carcinoma, including patients with pT2-T4a or lymph node positive after neoadjuvant chemotherapy and pT3-4 and lymph node positive patients who were not suitable/rejected to receive neoadjuvant cisplatin chemotherapy
.

The results showed that the median DFS of the nivolumab group and the placebo group were 21 months and 10.
9 months, respectively (HR=0.
7, P＜0.
002), and the median DFS of the two groups of PD-L1 patients were not reached.
And 10.
8 months (HR=0.
53, P＜0.
001)
.

01 Summary For patients with high-risk muscle invasive bladder cancer who have not received neoadjuvant chemotherapy, neoadjuvant chemotherapy is recommended; for patients who are intolerant to cisplatin and patients with muscle invasive bladder cancer who do not respond well to neoadjuvant chemotherapy, postoperatively Consider choosing adjuvant immunotherapy
.

Contribution email: tougao@medlive.
cn