Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open-label, single-arm, single-center, phase 2 study.

BACKGROUND: Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676). PATIENTS AND METHODS: After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively. RESULTS: From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9-58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0-69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6-NR), nor was median overall survival (interquartile range: 30.3-NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response (P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution. CONCLUSIONS: SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.

Prognostic Factors of Adjuvant Taxane, Cisplatin, and 5-Fluorouracil Chemotherapy for Patients With Penile Squamous Cell Carcinoma After Regional Lymphadenectomy.

BACKGROUND: Little is known about the outcomes and prognostic factors of adjuvant chemotherapy for locally advanced penile squamous cell carcinoma after regional lymphadenectomy (LAD). PATIENTS AND METHODS: We retrospectively reviewed the data from 21 patients who had received taxane, cisplatin, and 5-fluorouracil (TPF, every 3 weeks) in the adjuvant setting at our center. Univariable and multivariable Cox regression analyses were undertaken for disease-free (DFS) and overall survival (OS) of TPF. RESULTS: The patients had received TPF from July 2004 to July 2012 after inguinal (n = 6) or inguinal plus pelvic LAD (n = 15), and the median follow-up was 52 months. Thirteen (61.9%) had pelvic and 5 (23.8%) bilateral inguinal nodal metastases. The median time from LAD to the start of TPF was 5.4 weeks (interquartile range [IQR], 4.1-7.3 weeks). Metastatic tumor tissue from 11 of 19 evaluable patients (57.9%) showed positive immunohistochemistry staining for p53. Univariably, only the expression of p53 showed a trend toward poorer DFS (hazard ratio [HR], 4.14; 95% confidence interval [CI], 0.87-19.68; P = .074) and OS (HR, 4.54; 95% CI, 0.95-21.56; P = .056). The same results were obtained multivariably for DFS (HR, 3.76; 95% CI, 0.78-17.96; P = .096) and OS (HR, 4.29; 95% CI, 0.89-20.57; P = .067). The median DFS was 8.9 months (IQR, 5.9-22.7 months) for p53-expressing patients versus not estimable for non-p53-expressing patients (P = .051) and the median OS was 17.2 months (IQR, 12.8-22.7 months) and not estimable, respectively (P = .037). CONCLUSION: In patients who had received adjuvant TPF for node-positive penile squamous cell carcinoma, p53 IHC expression seemed to be associated with a poorer outcome, and further study is warranted in larger data sets to confirm these findings. This information might be useful to improve the prognostic allocation.

A Combination of Cisplatin and 5-Fluorouracil With a Taxane in Patients Who Underwent Lymph Node Dissection for Nodal Metastases From Squamous Cell Carcinoma of the Penis: Treatment Outcome and Survival Analyses in Neoadjuvant and Adjuvant Settings.

BACKGROUND: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF (a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings. PATIENTS AND METHODS: Since June of 2004, T-PF was administered to stage N2 to 3 patients. With time, neoadjuvant chemotherapy administration prevailed with respect to use in the adjuvant setting. Primary end points were progression-free (PFS) and overall (OS) survival. Secondary objectives were tolerability and activity in the neoadjuvant setting. Nonparametric tests, Kaplan-Meier, and regression analyses were performed. RESULTS: As of October of 2012, 47 consecutive N2 to 3 M0 patients had undergone neoadjuvant (n = 28) or adjuvant (n = 19) T-PF: 18 patients (38.3%) remain disease-free after a median follow-up of 22 months (interquartile range, 17-42 months). The 2-year disease-free survivals were 36.8% (95% confidence interval [CI], 15.2-58.5) versus 7.1% (95% CI, 0-16.7) after adjuvant and neoadjuvant therapy, respectively. N3 metastases were associated with a poorer PFS, and bilateral metastases and mutated p53 were associated with a poorer OS. After neoadjuvant treatment, 43% clinical responses and 14% complete pathologic remissions were recorded, but responses were not associated with survival. Neutropenia (25.5%) was the most frequent Grade ≥ 2 toxicity. CONCLUSION: The T-PF regimen is well tolerated and compares with other regimens in terms of activity and efficacy in the neoadjuvant setting, and very long survivals have been recorded after adjuvant administration. The role of perioperative treatment in these patients remains controversial. Some caution in administering preemptive treatment in patients with resectable disease is needed.