Abstract
Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.
Highlights
Many randomized trials have shown that carboplatin-based therapy is inferior compared with cisplatin in terms of overall survival (OS) and pathological complete response (pCR); that is why some authors proposed a more tolerated reduced dose of cisplatin 50 mg/m2 : a sequential ifosfamide, doxorubicin, and gemcitabine followed by reduced-dose cisplatin, gemcitabine, and ifosfamide resulted in similar oncological outcomes, with a pathological downstaging to pT1N0 disease or lower occurring in 50% of pts who underwent radical cystectomy (RC) [44,45] Despite these data, nowadays in cisplatinineligible pts, the standard of care re-mains to be upfront RC, with a higher risk of systemic relapse [5,6]
Consensus statements, bladder cancer (BC) with small-cell neuroendocrine variant should be treated with neoadjuvant chemotherapy followed by consolidating local therapy; muscle-invasive puresquamous cell carcinoma and pure-adenocarcinoma of the bladder should be treated with primary RC and lymphadenectomy [5]
Neoadjuvant platinum-based chemotherapy represents the standard treatment for non-metastatic muscleinvasive bladder cancer (MIBC) [77]
Summary
Since the 1980s, when cisplatin-based chemotherapy (CT) was introduced for MIBC treatment, only few steps forward have been taken. Clinical and pathological predictive markers to identify pts eligible for NAC therapy are not available yet [8]. Translational-based research approaches have made great efforts in building up the concept of personalized medicine for oncology pts, suggesting new prognostic and predictive biomarkers; novel targets, and introducing new therapies, such as immunotherapy-based ones. DNA and RNA sequencing of BC specimens showed the complex genetic heterogeneity of BC and identified specific profiles based on the type and frequency of mutations, on gene copy numbers and on the methylation patterns that could be helpful to define patient prognosis and sensitivity to specific treatments [9]. MIBC harbors a higher overall mutation rate and number of chromosomal aberrations than NMIBC, mainly involving the activation of prosurvival pathways such as p53, Rb, Pi3k-mTor, and RAS [10]
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