Date Published: February 13, 2012
Publisher: Hindawi Publishing Corporation
Author(s): James S. Chang, Primo N. Lara, Chong-Xian Pan.
Platinum-based chemotherapy is commonly used for the treatment of locally advanced and metastatic bladder cancer. However, there are currently no methods to predict chemotherapy response in this disease setting. A better understanding of the biology of bladder cancer has led to developments of molecular biomarkers that may help guide clinical decision making. These biomarkers, while promising, have not yet been validated in prospective trials and are not ready for clinical applications. As alkylating agents, platinum drugs kill cancer cells mainly through induction of DNA damage. A microdosing approach is currently being tested to determine if chemoresistance can be identified by measuring platinum-induced DNA damage using highly sensitive accelerator mass spectrometry technology. The hope is that these emerging strategies will help pave the road towards personalized therapy in advanced bladder cancer.
Bladder urothelial cancer is the 4th most common cancer in males and 9th in females and a major cause of morbidity and mortality worldwide. In the United States, approximately 70,530 individuals were diagnosed with bladder cancer in 2010 and 14,680 died from it . Most bladder cancers in the developed world are of urothelial origin (transitional cell), arising from the epithelial lining. Bladder cancers are broadly classified as noninvasive or invasive (muscle-invasive and metastatic) cancers. The noninvasive and invasive subtypes are thought to arise from distinct biological pathways . About 70 to 80% of newly diagnosed bladder cancers are noninvasive. The initial treatment of noninvasive cancer involves a complete transurethral resection followed by adjuvant intravesical therapy . As many as 70% of noninvasive cancers recur, necessitating life-long surveillance, and up to 25% will progress to more advanced disease [4, 5].
The current standard treatment in the United States for muscle-invasive bladder cancer is radical cystectomy with bilateral pelvic lymph node dissection. These patients often develop metastatic disease despite aggressive surgical intervention. In organ-confined pT2 disease, the 5-year survival rate is approximately 68% . Patients with more deeply invasive tumors have lower five-year survival rates of 30 to 50% . Relapse is due to the presence of occult micrometastases.
The standard treatment for patients with metastatic bladder cancer is systemic chemotherapy. Although bladder cancer is a chemosensitive tumor, the median survival with chemotherapy is only around 14 months. The five-year survival rate remains poor at about 15% . Cisplatin-based combination therapy is considered first-line based on a prospective randomized trial that compared cisplatin alone to MVAC in 269 patients . Patients treated with MVAC had significant improvement in response rate (39 versus 12%), PFS (10 versus 4.3 months), and overall survival (12.5 versus 8.2 months). Toxicity is a major concern with the MVAC regimen, particularly leukopenia, febrile neutropenia, mucositis, and nausea/vomiting. Only 24% of the patients received full-dose MVAC without dosage modifications. Five patients (4%) in the MVAC group plus 2 patients who were switched over to the MVAC regimen died from treatment-related toxicity.
Currently, chemotherapy for bladder cancer is taking the approach of one formula for all. Most patients presently receive a platinum-based regimen, usually GC. However, only about half of the bladder cancers will respond to chemotherapy. Extensive research is ongoing to better understand the biology of the disease process in order to improve clinical outcomes. Conventional prognostic factors such as the grade and stage of the tumor and tools like nomograms are useful in predicting the outcomes associated with surgery and the risk of recurrence but are inadequate in predicting response to chemotherapy [29, 30]. Biomarkers have the potential not only to further identify high-risk bladder cancer patients, but also to help select therapy for those who will benefit most from it. A personalized approach to chemotherapy has the potential to reduce toxicity and improve clinical outcomes (Table 1).
Cancer therapeutics is moving towards personalized medicine to select the most effective therapy while avoiding the ineffective and/or toxic therapy based on the underlying pathophysiology of the patients and their tumors. In bladder cancer, questions remain about who will benefit most from chemotherapy as only around 50% of bladder cancer patients will have tumor response from chemotherapy. Biomarkers have shown promise in prognostication and in selecting therapy and might help answer some of these questions. For example, ERCC1 status may be important to be determined before giving platinum-based chemotherapy, or hENT1 or RRM1 before gemcitabine. Combinations of biomarkers (including microRNA) can offer more accuracy in prediction than individual ones. Our group is using a microdosing approach to identify resistance to platinum drugs [79, 80]. The efficacy needs to be determined in large clinical trials. A better understanding of tumor biology and pathogenic pathways will hopefully lead to more molecularly targeted therapy. Research is ongoing to test agents that target the fibroblast, epidermal, and vascular endothelial growth factor pathways . The hope is that in the future targeted therapy will augment cytotoxic chemotherapy and that biomarkers will be able to risk stratify patients and help optimize therapy.