Tislelizumab has been approved by the China NMPA as a treatment for nine indications , including relapsed or refractory classical Hodgkin lymphoma (R/R cHL), locally advanced or metastatic urothelial carcinoma (UC) after failure of platinum-based chemotherapy, squamous non-small cell lung cancer (NSCLC), driver gene negative non-squamous NSCLC, hepatocellular carcinoma (HCC), non-small cell lung cancer (NSCLC), previously treated microsatellite instability-high (MSI-H) or mismatch repair gene-deficient (dMMR) advanced stage solid tumors, esophageal squamous cell carcinoma (ESCC), and nasopharyngeal carcinoma (NPC). Although tislelizumab is not approved for use outside of China, it has been submitted for regulatory review as a potential treatment for unresectable recurrent locally advanced or metastatic ESCC after prior systemic therapy in the USA, and in NSCLC and ESCC in Europe.
Bladder cancer is a common tumor of genitourinary system, with a median diagnosis age of slightly more than 70 years . Advanced age and medical comorbidities might pose the question of whether treatment should be recommended or not. In a study of 126 patients with muscle-invasive bladder cancer (64 patients did not receive any definitive local treatment, 62 patients received radical cystectomy or radiation therapy), Martini et.al. revealed that untreated patients had an increased risk of progression to metastatic disease (hazard ratio [HR] 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and cancer-specific mortality (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004) . Thus, the appropriateness of treatment should always be discussed, given the extremely poor prognosis if the disease is left untreated.
There are two primary routes of bladder cancer metastasis: one is via the lymphatic drainage system to regional lymph nodes, and the other is via the bloodstream to metastasis to distant organs. Tumor-associated lymphangiogenesis, tumor cell epithelial-mesenchymal transition (EMT), and tumor microenvironment are the key processes of lymph node metastasis . The most frequent sites of metastases were regional lymph nodes (90%), liver (47%), lung (45%), bone (32%), peritoneum (19%), pleura (16%), kidney (14%), adrenal gland (14%), and the intestine (13%) , whereas brain metastases are uncommon , and cardiac metastasis has not been reported.
Due to the capacity of the blood-brain and blood-tumor barriers to protect tumor cells from systemic chemotherapeutic medicines, the brain serves as a sanctuary site for metastatic tumor cells . Sternberg et al. reported in 1989 that MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) treatment resulted in brain metastases in 16% of 121 patients with advanced bladder transitional cell carcinoma (TCC) . Dhote et al. reported in 1998 on 50 patients with advanced TCC treated with the MVAC chemotherapy regimen, 8 (16%) of whom developed brain metastases . They discovered that brain metastases from bladder cancer frequently emerge late in the disease course, possibly due to MVAC medications' inability to cross the blood-brain barrier, increasing the risk of brain metastases. Diamantopoulos et al. also believed that, due to the protective effect of the blood-brain barrier, the central nervous system may favor the development of dormant and particularly drug-resistant malignant cells, resulting in tumor metastasis in the central nervous system . Sarmiento et al. described a patient who developed solitary brain metastases from transitional cell carcinoma 14 years after receiving gemcitabine for bladder cancer, implying that chemotherapeutic agents such as gemcitabine, which can cross the blood-brain barrier, may delay the development of brain metastases . Rosiello et al. investigated 5767 patients with metastatic bladder cancer in the USA and concluded that, unlike lung, bone, and other organ metastases, central nervous system metastases are not associated to race or age .
Brain metastases are primarily exhibited clinically as nausea, vomiting, headache, ataxia, disorientation, seizures, and loss of consciousness, as well as focal neurological symptoms (hemiplegia, blindness, cranial nerve palsy) and meninges due to meningeal carcinomatosis . Because brain metastases are uncommon in bladder cancer patients and head CT or MRI are not routinely performed, doctors should be aware of the possibility of brain metastases in patients presenting with neurological symptoms and complete head CT or MRI promptly. The current standard of care for brain metastases consists mostly of surgery, systemic chemotherapy, and whole brain or stereotactic irradiation, which may be administered alone or in combination . In a retrospective study of 16 patients with brain metastases from bladder cancer, surgery was found to be superior to radiotherapy alone . Another study of 62 patients with bladder cancer who developed brain metastases revealed no significant difference in overall survival or intracerebral control between surgical resection with radiation therapy and radiation therapy alone . While Rades et al. found no statistically significant difference between whole-brain irradiation plus a boost to the metastatic site and whole-brain irradiation plus radiosurgery in bladder cancer patients with solitary brain metastases, the former may be a better treatment option due to its less invasiveness . At present, there is still no consensus on the treatment of bladder cancer patients with brain metastases. Patients treated with chemotherapy had a median survival of 2–4 months, and patients with multiple brain metastases had a worse prognosis than patients with single brain metastases [6, 7].
The incidence of cardiac metastases in cancer patients exceeds 10%, which is significantly greater than the incidence of primary heart malignancies [27, 28]. Hematogenous metastases are common in melanoma, lymphoma, and sarcoma, which can lead to myocardial and endocardial involvement. Lymphoid metastases are common in lung cancer and can result in pericardial and epicardial involvement. Metastasis to the right atrium via the inferior vena cava is common in renal cancer, liver cancer, uterine leiomyoma and pheochromocytoma. Direct invasion can be seen in locally invasive tumors such as mediastinal and pleural tumors and breast cancer . The most common tumors that metastasize to the heart are lung cancer (37%), breast cancer (7%), esophageal cancer (6%), and hematological malignancies such as lymphoma (20%) . Because bladder cancer heart metastases have not previously been described, our case is likely to be the first, which may be disseminated through blood.
Over 90% of secondary cardiac tumors are clinically asymptomatic and are typically discovered until after death . Patients may present with nonspecific symptoms, distant embolism symptoms, or direct tumor invasion symptoms, such as blockage, cardiac tamponade, and arrhythmias . Clinicians should be aware of the risk of cardiac metastases in cancer patients who have new-onset cardiac symptoms and should choose further examinations, such as echocardiography, CT, or MRI, based on individual circumstances. Cardiovascular metastases have a 5-year survival rate of 26% in patients with advanced malignancies, and while the goal of treatment is to alleviate symptoms and prevent tumor recurrence, outcomes are usually unsatisfactory . For cardiac tamponade, immediate pericardiocentesis is required, followed by topical chemotherapy drugs or radioisotopes to prevent recurrence . For life-threatening arrhythmias, antiarrhythmic drugs should be used first, and radiofrequency ablation should be performed for uncontrolled arrhythmias . Due to the generally poor prognosis associated with cardiac metastases, radical surgery is rarely considered. Miralles et al. performed complete and incomplete resection for 2 patients with metastatic cardiac cancer, but died 1 month and 5 days after surgery, respectively . However, for patients with intracardiac obstruction, a positive prognosis, a resectable tumor, and no metastases to other sites, surgery is the preferred therapeutic option . Furthermore, in some cases, chemoembolization of a single heart mass supplied by coronary arteries may be advantageous .
Previous studies have demonstrated that second-line ICI treatment can significantly improve patient survival and may even be more effective in patients with high PD-L1 expression [9,10,11,12,13]. A recent meta-analysis revealed that PD-1 or PD-L1 inhibitors can reduce risk of both disease progression and death of patients with brain metastases of NSCLC . The clinical trial CTR20170071 enrolled 104 Asian patients with locally advanced or metastatic urothelial cancer who had previously received platinum-containing chemotherapy. The results indicated that tislelizumab treatment had a 24.8% objective response rate (ORR) and a 38.6% disease control rate (DCR) . However, despite the fact that the majority of patients (76%) in this trial had visceral metastases, including 24% with liver and 23% with bone metastases, no patients with brain or heart metastases were included. In this study, we report the first case of tislelizumab being beneficial for urothelial carcinoma with brain and heart metastases. Despite receiving first-line chemotherapy, we think that surgically treated patients with cerebral and intracardiac lesions have a poor prognosis. Given Tislelizumab’s remarkable efficacy in the treatment of advanced bladder cancer, it was decided to begin systemic immunotherapy after consulting with the doctor and obtaining patient consent. After 6 cycles of systematic tislelizumab immunotherapy, re-examination revealed that the patient’s right temporal lobe lesions significantly decreased, bilateral frontal lobe lesions vanished, left cerebellar hemisphere lesions stabilized, the left atrial mass resolved, and the dizziness and headache resolved, with no recurrence of symptoms of loss of consciousness or arrhythmia. It has been 16 months since the patient was diagnosed with brain metastasis and heart metastasis of bladder cancer by the time this article was written, and the general condition of the patient is still good. His survival time has far exceeded the documented general survival time of brain metastatic cancer patients undergoing surgery or chemotherapy, and he also survived far longer than heart metastatic cancer patients undergoing surgery. We believe that the benefit of tislelizumab immunotherapy may outweigh the benefit of surgical excision of metastases, especially head and heart metastases, for which the effect of chemotherapy, radiotherapy and surgery is poor, but more study is needed to validate this.
Additionally, unlike other anti-PD-1 antibodies, tislelizumab was specifically engineered to minimize Fcγ receptor binding to limit antibody-dependent phagocytosis, a mechanism of potential resistance to anti–PD-1 therapy [39, 40]. We speculate that this property contributes to its inhibitory effect on distant metastasis. However, we cannot make sure whether earlier tislelizumab treatment would have been more effective at preventing tumor metastasis in this patient. To maximize the benefits for bladder cancer patients, we anticipate more clinical trials evaluating early-stage and neoadjuvant/adjuvant immunotherapy will be conducted in the future.