In 2015, the NCCN released two editions of its guidelines for the diagnosis and treatment of bladder cancer, and the new edition of the guidelines contains some updates on the diagnosis and treatment of bladder cancer. Compared to urologic tumors such as kidney cancer and prostate cancer, there have been fewer treatment breakthroughs in bladder cancer, especially in advanced bladder cancer, but there are still continued developments.
Although China has a large population and is the second largest country in terms of new bladder cancer patients, WHO data show that our country is the number one country in terms of bladder cancer deaths, so standardized treatment of bladder cancer, especially in the progressive stage, is especially urgent. In this article, we will explain the medical treatment section of the guidelines so that medical oncologists and urologic oncologists in China can better understand and follow the guidelines, and improve the understanding of medical treatment of bladder cancer so that patients can benefit.
1. Neoadjuvant chemotherapy for bladder cancer
Chemotherapy is an important component of treatment for patients with muscle-invasive bladder cancer. There is growing evidence to support neoadjuvant chemotherapy for bladder cancer staged T2 or T3 prior to total bladder resection. Two randomized clinical studies have shown a survival benefit of neoadjuvant chemotherapy, particularly for lesions with clinical stage T3. One included 307 bladder cancers with muscle invasion randomized to radical bladder resection alone or surgery after 3 cycles of preoperative MVAC regimen neoadjuvant chemotherapy and showed that neoadjuvant chemotherapy improved median survival (77 vs 46 months) and significantly reduced lesion residual rates, while neoadjuvant chemotherapy did not increase treatment-related mortality. An additional meta-analysis involving 11 clinical studies of 3005 patients with bladder cancer showed that cisplatin-based neoadjuvant chemotherapy improved 5-year survival as well as disease-free survival. Therefore, the 2015 edition of the NCCN guidelines recommends cisplatin-based neoadjuvant chemotherapy as a level 1 evidence for patients with bladder cancer at T2 stage and beyond. For patients with renal insufficiency, the NCCN guidelines do not recommend carboplatin as an alternative to cisplatin in neoadjuvant chemotherapy, and such patients are not recommended for neoadjuvant chemotherapy.
As for specific regimen dosing, in addition to traditional MVAC regimens, dose-dense MVAC regimens are better tolerated, and a multicenter prospective phase II clinical study showed that dose-dense MVAC regimens have a better safety profile and shorter time to surgery, while obtaining similar pathologic CR rates. Another international multicenter randomized clinical trial (BA06 30894) investigated the efficacy of neoadjuvant chemotherapy with cisplatin + methotrexate + vincristine (CMV) regimen and enrolled 967 patients with a 16% lower risk of death in patients receiving neoadjuvant CMV regimen preoperatively. Although there are no large clinical studies of neoadjuvant chemotherapy with GC regimens, combined with previous studies showing the equivalence of GC regimens to traditional MVAC regimens, the recommended neoadjuvant chemotherapy regimens are dose dense MVAC (DDMVAC) regimens, GC regimens or CMV regimens for 3-4 cycles.
2. Bladder-preserving chemotherapy strategy
Radiotherapy combined with cisplatin-based concurrent chemotherapy (as a radiosensitizer) is currently the most common and most studied treatment regimen for bladder preservation in muscle-invasive bladder cancer. After complete TURBT, 40 Gy of external irradiation (often 4 radiotherapy fields) is administered; and two cycles of cisplatin-based regimens of synchronized chemotherapy are given at weeks 1 and 4. After these induction treatments, endoscopic evaluation is repeated, and if no tumor is seen on cystoscopy and cytology and biopsy are negative, 25 Gy of consolidating external irradiation radiotherapy combined with one cycle of cisplatin-based chemotherapy is added. Several prospective clinical studies have shown this approach to be effective, such as the RTOG 89-03 study as well as the RTOG 97-06 study.
The following radiotherapy sensitization regimens are all currently considered for simultaneous radiotherapy for bladder preservation after maximal TURBT: cisplatin (class 2A recommendation), cisplatin + 5-FU (class 2A recommendation), 5-FU + mitomycin (class 2A recommendation), cisplatin + paclitaxel (class 2B recommendation), and low-dose gemcitabine (class 2B recommendation). If there are suitable clinical studies, it is recommended to join.
3.Postoperative adjuvant chemotherapy for bladder cancer
For postoperative adjuvant chemotherapy for bladder cancer, the level of evidence for postoperative adjuvant chemotherapy for bladder cancer is not as good as that for neoadjuvant chemotherapy because there are no randomized large sample clinical studies showing a survival benefit from systemic adjuvant chemotherapy, and some corresponding clinical studies have conflicting findings that do not confirm at this stage that adjuvant chemotherapy can delay recurrence or prolong survival.
It is generally accepted that patients with bladder cancer with pathologic staging of T2 and below and without lymph node metastases are at low risk of recurrence and are not recommended to receive postoperative adjuvant chemotherapy. However, current data suggest that adjuvant chemotherapy may be able to delay tumor recurrence and metastasis, so the application of adjuvant chemotherapy for recurrent and high-risk patients is feasible. It has been demonstrated that postoperative adjuvant chemotherapy in this group of high-risk patients can reduce mortality by 30%, especially if such patients do not receive neoadjuvant chemotherapy preoperatively, and postoperative adjuvant chemotherapy is usually recommended with level 2B evidence of recommendation.
Overall for patients with pathologic stage T3 and above, or lymph node metastases, at least three cycles of cisplatin-based combination regimen chemotherapy (e.g., MVAC or the more common GC regimen) may be used in adjuvant therapy due to their high risk of recurrence. The regimens of choice are CAP (cyclophosphamide + doxorubicin + cisplatin), MVAC regimen, MVEC regimen (methotrexate + vincristine + epirubicin + cisplatin), and GC regimen (gemcitabine + cisplatin). There is a lack of evidence to support the application of adjuvant chemotherapy in non-uroepithelial carcinoma of the bladder (regardless of any stage).
4.Treatment of metastatic bladder cancer
For treatment of inoperable and metastatic bladder cancer, chemotherapy-based combination therapy should be used. The MVAC regimen was commonly used in the past, but since the introduction of chemotherapeutic agents such as gemcitabine and paclitaxel, new chemotherapy regimens have challenged the original regimen. A randomized controlled phase III clinical study comparing GC regimen with standard MVAC regimen for advanced bladder cancer showed that the objective effective rate was 49% versus 46%, and the median survival time was 14.0 months versus 15.2 months, and the median PFS time was 7.7 months versus 8.3 months, respectively, with no significant difference between the two groups. The GC regimen was confirmed to be equivalent to the standard MVAC regimen, while the GC regimen was significantly better than the MVAC regimen in terms of tolerability. In another phase III clinical study comparing the dose-dense MVAC regimen with the standard MVAC regimen, the median follow-up was 7.3 years, with survival rates of 24.6% versus 13.2%, and the dose-dense MVAC regimen was better tolerated. Based on the two randomized controlled clinical studies, the NCCN guidelines recommend the dose-dense MVAC regimen versus the GC regimen as Class 1 evidence for first-line chemotherapy in inoperable or metastatic bladder cancer. In patients with renal insufficiency, gemcitabine in combination with carboplatin and methotrexate in combination with carboplatin and vincristine have objective efficacy rates of 42% and 30%, so the NCCN guidelines consider carboplatin as an alternative to cisplatin in patients with renal insufficiency.
Paclitaxel is also an effective chemotherapeutic agent for bladder cancer, and paclitaxel combined with cisplatin and paclitaxel combined with gemcitabine have been validated in phase I/II clinical studies. As for the three-drug combination regimen (PCG) of paclitaxel combined with cisplatin and gemcitabine, a phase III randomized controlled clinical study (ECORT30987) compared whether it was superior to the GC regimen for metastatic uroepithelial carcinoma and showed that the objective efficiency was 55.5% versus 43.6%, the median overall survival time was 15.8 versus 12.7 months, and the median PFS time was 8.3 versus The incidence of neutropenia was significantly higher in the three-drug treatment group than in the GC regimen, so the NCCN guideline expert committee considered that patients had limited benefit from PCG regimen treatment and did not recommend it. However, subgroup analysis of patients with metastatic uroepithelium with primary lesions originating from the bladder showed a significantly better median OS in the PCG treatment group than in the GC treatment group (15.9 vs. 11.9 months), so the PCG regimen may still be beneficial for some patients. Although not recommended by NCCN guidelines, based on this trial, the above regimen without cisplatin, i.e., paclitaxel combined with gemcitabine, could be recommended as first-line treatment for patients with renal insufficiency or other comorbidities in combination, with a recommendation level of 2B.
For second-line treatment of metastatic bladder cancer, no standard treatment recommendation has been made, and NCCN guidelines strongly recommend that patients participate in the appropriate clinical studies. In actual clinical practice, if there are no corresponding clinical studies, single-agent regimens such as single-agent docetaxel, paclitaxel or gemcitabine can be selected as second-line agents based on the first-line regimen use, but the efficacy of second-line chemotherapy is limited and more effective treatment options still need to be explored. Although immune checkpoint inhibitors, such as PD-L1 monoclonal antibody and PD-1 monoclonal antibody, are promising for second-line treatment of uroepithelial cancer, there are no corresponding phase III clinical trial data and the guidelines do not make corresponding recommendations.
Patients with metastatic bladder cancer need to be evaluated after 2-3 cycles of chemotherapy, and if the lesion shrinks or stabilizes on review, the original regimen should be continued for 2 cycles of chemotherapy. Patients with unresectable primary lesions initially but who achieve a large PR (partial remission) after chemotherapy, as well as those with only isolated resectable lesions remaining after chemotherapy, may be considered for surgery or radiation therapy, which may provide a survival benefit with the above management modalities. After complete resection of the lesion, 2 additional cycles of chemotherapy may be considered depending on the patient’s tolerability. For patients not considering surgery or radiotherapy, a maximum of 6 cycles of chemotherapy is usually recommended, depending on the efficacy of the drug. If treatment is ineffective after 2 cycles or if serious adverse effects occur, a change of treatment regimen is recommended, taking into full consideration the patient’s general condition, the extent of the lesion and the first-line treatment regimen.
5.Chemotherapy for non-uroepithelial origin bladder cancer
The pathological type of bladder cancer is mainly uroepithelial cancer, but there are still a small number of non-uroepithelial cancer pathological types, including adenocarcinoma as well as squamous carcinoma. The treatment of these patients should be pathologically based and multidisciplinary, with surgery still being the mainstay, radiotherapy being an important component of treatment, and chemotherapy being practiced sparingly, usually with regimens sensitive to these pathological types, such as squamous carcinoma, with fluorouracil as well as paclitaxel. Overall, recommendations for systemic chemotherapy remain more valid for non-uroepithelial types of bladder cancer.
6. Summary
Every year, NCCN treatment guideline recommendations for various types of tumors are widely followed. For bladder cancer, the treatment of progressive bladder cancer, especially the progress of medical treatment should be far less than other common tumors, expecting effective second-line treatments such as targeted therapy and immunotherapy, but based on current evidence-based medicine, NCCN still needs to further standardize the medical treatment for bladder cancer in China, emphasizing multidisciplinary comprehensive treatment is still the basic consensus for the treatment of progressive bladder cancer.