Epidermal growth factor receptor inhibitor with fluorouracil, leucovorin, and irinotecan as an alternative treatment for advanced upper tract urothelial carcinoma: a case report

Currently, there is no standard salvage regimen after the failure of cisplatin-based chemotherapy for advanced urothelial carcinoma. Many novel agents have been developed and have shown modest activity in urothelial carcinoma. With the advancement of molecular biology and a deeper understanding of the pathogenesis of urothelial carcinoma, new approaches for treating patients using molecularly targeted therapies have emerged. Previous studies have shown that the over-expression of epidermal growth factor receptor (EGFR) predicts poor survival and stage progression [4, 5]. EGFR is more strongly expressed in invasive tumors (pT2–T4) and high-grade tumors than in superficial or low-grade tumors [4]. However, mutations within the kinase domain and truncations of the EGFR are rarely seen in bladder cancer, and they have emerged as attractive therapeutic targets. Cetuximab (an EGFR inhibitor) is a chimeric human/mouse monoclonal antibody that prevents dimerization by binding to the extracellular domain of EGFR. Wong et al. [6] conducted a phase II clinical trial to evaluate the efficacy of cetuximab with or without paclitaxel as salvage chemotherapy in patients with previously treated advanced urothelial cancer. The study was closed after 8 weeks, because 9 of 11 patients had disease progression in the paclitaxel-alone arm. Progression-free survival greater than 16 weeks was noted in 12 of 28 patients in the combination arm. They concluded that cetuximab may augment the activity of paclitaxel, and the combination merits further study as salvage chemotherapy in patients with previously treated urothelial carcinoma. Although the mechanisms are unclear, it seems that cetuximab is not effective for use as a single-agent therapy. Another phase II clinical trial (clinicaltrials.gov ID: NCT00645593) is investigating this augmentation by evaluating the effect of gemcitabine and cisplatin chemotherapy either in combination with cetuximab or not in patients with locally advanced or metastatic urothelial cancer (above stage T4b), and results are pending. To date, there have been at least eight clinical trials aimed at treating urothelial carcinoma by targeting EGFR (https://​clinicaltrials.​gov/​ct2/​results?​term=​Bladder+cancer+A​ND+epidermal+gro​wth+factor+recep​tor&​Search=​Search).

Despite the widespread implementation of traditional cisplatin-based chemotherapy, other clinical trials have included synchronous chemotherapy using fluorouracil and mitomycin C combined with radiotherapy. These trials demonstrated significant improvements in the control of bladder cancer compared with radiotherapy alone [7]. Gemcitabine-based and carboplatin-based regimens have also been studied; Sio et al. [8] demonstrated a 61 % response rate with the combination of gemcitabine and irinotecan.

The Cancer Genome Atlas project performed an integrated analysis of 131 urothelial carcinoma cases to provide a comprehensive landscape of molecular alterations [9]. They determined that 69 % of the tumors could potentially be treated, through the use of therapy targeted to the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway in 42 % of the tumors or targeted to the RTK/MAPK pathway (including ERBB2) in 45 % of the tumors. They also found that urothelial carcinoma had more frequent mutations in chromatin regulatory genes. The current findings all suggest the future possibility of targeted therapy. The development of reliable molecular markers is expected to make personalized treatment strategies possible for the treatment of urothelial carcinoma. In our case, the unexpected treatment effect of cetuximab and FOLFIRI in urothelial carcinoma has not previously been reported. The urothelial carcinoma in this case harbored the wild-type form of KRAS, indicating its susceptibility to cetuximab.