Bladder cancer is the most common malignant tumor of the urinary system. More than 90% of patients with bladder cancer are metastatic epithelial carcinoma (TCC), while about 55% to 60% of patients first diagnosed with bladder cancer are superficial bladder cancer. Superficial bladder cancer is defined as all bladder cancers in stages T0G1 to T1G3, including in situ cancers. These patients have a high recurrence rate even after appropriate intracavitary or open treatment. Usually, recurrence is still superficial bladder cancer with good differentiation, but about 16% to 25% of patients have increased tumor pathologic grade, and about 10% of superficial bladder cancers develop muscle infiltration or distant metastases. It is extremely important to use different treatment methods for superficial bladder cancer according to different types.
1.Intracavitary treatment of superficial bladder cancer
1.1 Transurethral electrical resection (TURBt)
Most superficial bladder cancers can be treated by TURBt to remove the visible tumor cleanly. The 5-year survival rate after TURBt for such patients is about 70%, and about 10% to 15% of superficial bladder cancers eventually require treatment by a more invasive approach. Well-differentiated or better-stage Tis and Ta superficial bladder cancers have a lower chance of recurrence and infiltration, whereas the incidence of muscle infiltration in stage T1 superficial bladder cancers can be as high as 46%, especially in poorly pathologically differentiated G3 bladder tumors.
Thus high-risk bladder cancer (T1G3) should be considered as highly potentially invasive. Some authors suggest that some patients with superficial bladder cancer undergo TURBt, but in fact some of the tumor is still not completely resected. a study by Klan et al. concluded that 40% of patients who had been considered to have a clean TURBt resection were found to have localized tumor after six weeks of re-excision. TURBt is appropriate for all superficial bladder cancers that can be reached by cystoscopy, is less invasive to the patient, and can be repeated multiple times. performed.
The results are considered superior to those of partial cystectomy. Therefore, it can almost replace it. However, because of the recurrent nature of the tumor, especially in high-risk bladder cancer, adjuvant therapy and close follow-up after TURBt is mandatory.
1.2 Photodynamic therapy
Hematoporphyrin derivatives (HPD) are easily absorbed by malignant tumor cells and have a long storage time. After stimulated by laser at certain wavelengths, monomorphic oxygen is produced to damage mitochondria and kill tumor cells and their vascular system. It is also activated by white light and can be used to localize small cancer foci or in situ cancer foci. Photodynamic therapy requires 6 to 8 weeks of light avoidance after surgery.
The complications are mainly photosensitivity dermatitis and bladder contracture. 5-aminolerulinic acid (ALA) is a new photosensitizing substance that overcomes the disadvantages of HPD and has the advantages of non-allergy and no need for light avoidance. treated 10 patients with recurrence of bladder cancer. 10-12 weeks after treatment, 4 cases were cured, 2 cases were improved, 1 case was ineffective and 3 cases had progressed.
1.3 Laser treatment
More than ten kinds of lasers have been used for bladder tumor treatment. Laser treatment has the advantages of safety and simplicity, less bleeding, can be performed under surface anesthesia of the bladder, and will not stimulate the closed nerve causing accidental injury. The laser has no electric field effect and can be used for patients with cardiac pacemakers. Laser irradiation also blocks the tumor lymphatics, which prevents the spread of cancer cells. Superficial bladder tumors can be treated directly with holmium laser or Nd:YAG laser.
If the tumor is larger than 1.0 cm, TURBt can be performed first followed by laser vaporization and coagulation. The disadvantage of direct laser treatment is the lack of histopathological judgment due to the lack of direct access to histopathological specimens. Although some studies have concluded that laser and TURBt are equally effective in the treatment of superficial bladder cancer, the clinical application is far from popular as TURBt.
1.4 Intracavitary thermotherapy
The method of using a microwave-generating catheter at the head end to insert into the bladder to bring the temperature inside the bladder to 42.5 to 45.5°C while infusing chemotherapeutic drugs such as mitomycin has also achieved some efficacy.
2, superficial bladder cancer drug perfusion therapy
2.1 Single drug infusion
2.1.1 Chemical drugs The following chemical drugs are currently used.
(1) Thiotepa (TT) is the first intravesical chemotherapeutic drug used in the 1960s, which is an alkylating agent, mainly through cross-linking with the two strands of DNA to destroy DNA and affect the division of cancer cells. Routinely 60 mg dissolved in 60 ml saline infusion.
The application of thiotepa after TURBt can reduce the recurrence rate of tumor from 73% to 47%. However, it has also been reported that tiotepe has no significant efficacy regardless of the perfusion method. Tiotepe is still widely used in some areas because of its low local toxicity and low price. Due to its low molecular weight (198 Da), it is easily absorbed by the urinary epithelium and can cause bone marrow suppression in 15-20% of patients. Erythrocyte and platelet tests should be performed frequently during treatment.
(2) Mitomycin (MMC) is an antibiotic chemotherapy drug that inhibits DNA synthesis. Because of its molecular weight of 334 Da, it is rarely absorbed through the urinary epithelium causing toxic reactions such as bone marrow suppression. Mitomycin can be perfused immediately after TURBt treatment. It is equally effective with mitomycin in patients in whom thiotepa perfusion has failed.
Heney et al. compared the efficacy of thiotepa and mitomycin in 149 cases of superficial bladder cancer in two randomized groups and found that the complete response rate was 26% in the thiotepa group and 39% in the mitomycin group, and the partial response rate was 53% in the thiotepa group and 63% in the mitomycin group. However, the incidence of complications due to mitomycin was about 5% to 50%. The main manifestations are chemical cystitis, allergic reaction, bone marrow suppression and urethral stricture. Less common are bladder wall calcification and bladder volume reduction. Mitomycin is more expensive because of higher dosage.
(3) Adriamycin (ADM, DOX) is also an antibiotic chemotherapeutic agent with a molecular weight of 580 Da and very little absorption. The complete remission rate of perfusion chemotherapy is less than 50% and partial remission rate is less than 30%, and its side effects are mainly chemical cystitis, which can occur in about 50% of patients; a few patients can have severe bladder contracture.
The number of infusions varies from 3 times/week to 1 time/month and less than half of the patients can achieve complete remission and about 1/3 have partial remission. No significant difference in remission rates between high-graded and low-graded tumors for adriamycin has been reported.
(4) Epirubicin, a derivative of adriamycin, is considerably less toxic than adriamycin. Compared with adriamycin, there is no significant difference in the efficacy of the two in preventing postoperative recurrence, but they are better tolerated, and the incidence of chemical cystitis is about 5%.
(5) Other commonly used chemical agents are hydroxycamptothecine (Hydroxyl camptothecine) and ethylglyoxal (Epodyl, Etoglucid).
2.1.2 Bioreactive modifiers
Since 1976, when BCG bladder perfusion was first reported by Morale for the prevention of superficial bladder cancer, it is now accepted that BCG is the best method to prevent recurrence of superficial bladder cancer and to treat carcinoma in situ (Tis). Most controlled comparative studies have shown that intravesical BCG perfusion is satisfactory and that BCG is significantly more effective than other intravesical chemotherapeutic agents in reducing bladder cancer recurrence and preventing lesion progression. It should be considered as a first-line drug for treatment.
The tumor recurrence rate after TURBt is 42%, while the addition of BCG after TURBt can reduce the recurrence rate to 17%. Studies have shown that the application of BCG to prevent tumor recurrence can reduce the recurrence rate to 0-41%, with an average of 20%. BCG can also be used for the treatment of residual tumors and unresectable tumors, and its complete response rate is 58%.
The anti-tumor mechanism of BCG has not been fully elucidated. It is believed that BCG is a non-specific immunosuppressant with non-specific cytotoxic effects, and the direct contact between BCG and tumor cells and mucosal epithelial cells, as well as the acute inflammatory response of the bladder after contact, are the central aspects of the induced immune response. In addition BCG acts by increasing the expression of Fas receptors on the surface of tumor cells and inducing Fas and Fas ligand binding to mediate apoptosis of tumor cells.
BCG is administered by oral BCG, intratumoral BCG infusion plus intradermal injection, and intravesical bladder infusion. The most commonly used route is still intravesical bladder perfusion. 95% of the side effects and complications of BCG intravesical perfusion therapy are self-limiting. They can resolve or subside on their own when the BCG infusion interval is stopped or extended. The main side effects are: cystitis, febrile reaction, granulomatous prostatitis, ureteral obstruction, and bladder contracture.
The complete response rate of low-dose (60 mg) BCG infusion for the prevention and treatment of superficial bladder cancer is not significantly different from that of full-dose (120 mg) or high-dose (150 mg), but the BCG side effects are significantly reduced. a randomized controlled prospective study of 500 patients with superficial bladder cancer by Spanishoncologygroup, the application of 1/3 conventional In a randomized controlled prospective study of 500 patients with superficial bladder cancer, the application of 1/3 of the conventional dose significantly reduced local or systemic side effects without significant differences in tumor recurrence and progression.
The antitumor effects of interferon (IFN) may be mediated through direct inhibition of tumor cell growth in addition to the destruction of tumor cells by modulating host defenses. Interleukin-2 (IL-2) is a cytokine that, in addition to stimulating cell proliferation, leads to the proliferation and differentiation of killer T cells, activation of natural killer cells (NK), and induction of lymphokine-activated killer cells (LAK) and tumor-infiltrating lymphocytes (TIL) production.
It also plays an important role in immune regulation. It is mostly used in combination with BCG or other chemotherapeutic agents to improve the efficacy. Other biological response modifiers, such as tumor necrosis factor (TNF), LAK cells and TIL cells, are mostly expensive or of low efficacy, and are currently in the research stage and not widely used in clinical practice.
2.1.3 Single-course perfusion and single-course plus maintenance therapy
For single, low-grade primary or recurrent Ta and T1 bladder tumors, the most recent studies suggest that single-dose infusion chemotherapy immediately after TURBt is sufficient without maintenance infusion therapy.Oosterlinck et al. reported a controlled randomized group study of 451 cases of Ta and T1 bladder cancer, in which epoetin 80 mg was given as infusion immediately after TURBt, with a mean follow-up of 2 years. Tolley et al. reported similar findings with single-dose infusion of mitomycin.
Tolley et al. reported similar findings with a single dose of mitomycin infusion, which was applied as a single course of infusion for 6 weeks with BCG infusion once a week. The advantages are short duration of treatment and mild side effects. The efficacy of single dose (course) is similar to that of maintenance therapy, so it can reduce unnecessary pain and economic burden of patients. However, for superficial bladder cancer with high risk (T1G3), single dose (course) plus maintenance therapy can significantly improve the efficacy and complete response rate of superficial bladder cancer treatment.
2.2 Drug combination infusion chemotherapy
High-dose infusion of a single drug can easily cause serious toxic side effects. Combination of drugs can make use of different mechanisms of action of different drugs and act on different cell cycles, so that tumor cells are less likely to develop drug resistance, and at the same time can reduce the dose used and produce synergistic effects to improve the efficacy and achieve the purpose of reducing toxic side effects.
Sekine et al. used MMC+DOX combination and the complete response rate was 74%, which was considered more effective than MMC or DOX alone. The stimulation and modulation of nonspecific cellular immune responses by biological response modifiers can enhance the effects of chemical drugs.
Okamoto et al. found that combining IFN-a with MMC or ADM significantly increased the sensitivity rate to tumor cells, which was significantly better than that of the drug alone. The combination of biological response modifiers can also reduce complications and enhance immune response, and BCG+IL-2 and BCG+IFN combination perfusion can achieve better efficacy due to synergistic effects and reduce the dosage of BCG and toxic side effects.
3.Radiotherapy and internal iliac artery cannulation chemotherapy
Radiotherapy is rarely used in the treatment of superficial bladder cancer because of its unreliable efficacy and the possibility of radiation cystitis. Internal iliac artery cannulation chemotherapy is also rarely used in the treatment of superficial bladder cancer.
4.Radical resection for superficial bladder cancer
Although most scholars now believe that bladder preservation should be used for T1G3 bladder cancer, there are still some patients who deteriorate and progress with delayed treatment. Radical cystectomy should be performed before possible muscle infiltration and distant metastases to achieve a cure. radical cystectomy should be considered when TURBt and BCG and other chemotherapeutic agents have failed and the following indications are present.
① Recurrence of stage T1 tumor or de novo stage T1 tumor;
②Newly discovered Tis;
③Tumors located in areas that are difficult to be resected with TURBt such as the anterior bladder neck wall;
(iv) muscle infiltration.