Piera Federico

A comprehensive outlook on intracerebral therapy of malignant gliomas.

Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12-15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood-brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel(®), are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM.

Third-Line Sorafenib After Sequential Therapy With Sunitinib and mTOR Inhibitors in Metastatic Renal Cell Carcinoma

BACKGROUND Sunitinib and everolimus have been approved for first- and second-line treatment, respectively, in metastatic renal cell carcinoma (mRCC). The role of sorafenib, which is approved for second-line treatment after cytokines failure, is presently to be defined. OBJECTIVE To determine whether third-line sorafenib after sequential use of sunitinib and mammalian target of rapamycin inhibitors (everolimus or temsirolimus) is feasible and effective. DESIGN, SETTING, AND PARTICIPANTS One hundred fifty medical records of patients with mRCC treated with first-line sunitinib between January 2006 and January 2010 were reviewed at four participating centers. Data regarding patients treated with the sequence sunitinib-everolimus or temsirolimus-sorafenib were extracted. Central analysis of radiographic images was performed using RECIST criteria to determine progression-free survival (PFS) and overall response rate (oRR) to sorafenib treatment. MEASUREMENTS PFS and oRR to sorafenib were the primary end points. Secondary outcomes were safety and overall survival (OS). RESULTS AND LIMITATIONS Thirty-four patients were eligible for the study. A median PFS of 4 mo (range: 3-6 mo) and a median OS of 7 mo since sorafenib treatment (range: 6-10 mo) were reported. Of the patients, 23.5% showed response to sorafenib, with an overall disease control rate (complete responses plus partial responses plus stable disease) of 44%. Selection bias, data incompleteness, and absence of study design are inevitable limitations of the study, although central review can strengthen the quality of presented data. CONCLUSIONS Third-line sorafenib appears to be active and well tolerated in mRCC after first-line sunitinib and second-line everolimus or temsirolimus, with no patients interrupting sorafenib because of toxicity or lack of compliance. Prospective, placebo-controlled trials are completely lacking and are required in this setting.

Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis

Study Type – Therapy (case series)

Paclitaxel in Pretreated Metastatic Penile Cancer: Final Results of a Phase 2 Study

BACKGROUND Previously published preliminary findings showed promising activity of paclitaxel in chemotherapy-pretreated metastatic penile cancer. OBJECTIVE To evaluate the activity and safety of paclitaxel in pretreated metastatic penile cancer. DESIGN, SETTING, AND PARTICIPANTS Twenty-five patients were enrolled in a single-arm phase 2 multicentre study and treated with 175 mg/m² paclitaxel at 3-wk intervals until disease progression or irreversible toxicity. MEASUREMENTS The objective response rate was the primary end point. Safety, progression-free survival (PFS), and overall survival (OS) were secondary end points. RESULTS AND LIMITATIONS Partial responses were observed in 20% (5 of 25 patients). Grade 1-2 neutropenia, nausea, and oral mucositis were the most common side effects, noted in 13, 9, and 8 patients, respectively. Grade 3-4 neutropenia was reported in seven patients (28%). Median PFS was 11 wk (95% confidence interval [CI], 7-30); median OS was 23 wk (95% CI, 13-48). Median survival in responders was 32 wk (95% CI, 20-48). One limitation of our study was the limited accrual, which did not reach the target of 27 patients, due to the typical slow enrolment of a rare disease. CONCLUSIONS Final results of this study demonstrate that paclitaxel is moderately active and well tolerated. Further trials, which may also explore the combination of paclitaxel with other agents, are required to confirm our findings.

Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs)

BACKGROUND No previous prospective trials have been reported with capecitabine and gemcitabine (CAP-GEM) in patients with metastatic thymic epithelial tumors (TETs). We conducted a multicenter study to determine the activity and tolerability of this regimen in pretreated TETs. PATIENTS AND METHODS A total of 15 patients were enrolled in the first stage of phase II study. All patients received CAP-GEM every 3 weeks. The primary end point was objective response rate (RR); secondary end points were toxicity, progression-free survival (PFS) and overall survival. RESULTS Complete responses (CR) and partial responses were observed in three (20%) and three (20%) patients for a 40% RR, respectively. Grade 1-2 neutropenia, anemia and thrombocytopenia were the most common side-effects, noted in seven (46.7%), five (33.3%) and five (33.3%) patients, respectively. The most common grade 3 toxicity was neutropenia in three patients (20%). Median PFS was 11 months (95% confidence interval 4-17). The 1- and 2-year survival rates were 80% and 67%, respectively. CONCLUSION We have decided to publish the preliminary results because this regimen was more active than that expected. Although our results are preliminary, CAP-GEM shows activity and safety in pretreated TETs. Furthermore, multicenter trials, also in first-line setting, are necessary to confirm our results.

Potential value of Gleason score in predicting the benefit of cabazitaxel in metastatic castration-resistant prostate cancer.

AIM This study aimed to identify predictive/prognostic factors in castration-resistant prostate cancer patients treated with cabazitaxel. PATIENTS & METHODS Patients were enrolled from March 2011 to December 2011 in an international expanded access program. In January 2012, when cabazitaxel became commercially available, a prospective study was initiated at University Federico II of Naples and at Rionero in Vulture Hospital. RESULTS Forty-seven patients were enrolled in this study. Patients received a median of nine cycles of cabazitaxel. Median progression-free survival was 7.0 months (95% CI: 5.7-8.0). Seventeen patients were still alive at the time of the analysis, with a median overall survival of 14 months (95% CI: 11-16). At multivariate analysis, a higher Gleason score (≥ 8) appeared to be associated with prolonged progression-free survival (hazard ratio: 0.36; 95% CI: 0.18-0.72); however, the higher Gleason score showed no statistical impact on overall survival. CONCLUSION We hypothesize that the Gleason score has the potential to be incorporated in the clinical decision-making process for definition of treatment strategy in docetaxel-pretreated castration-resistant prostate cancer patients. We encourage further experimentation in this setting.

Combination of docetaxel and cetuximab for penile cancer: A case report and literature review

Guidelines on the treatment of metastatic squamous cell carcinoma of the penis are limited to a few prospective trials. Cisplatin-based regimens represent the standard of treatment with promising activity of taxanes. Recently, epidermal growth factor receptor overexpression has been shown in these patients. We treated an elderly man with a docetaxel–cetuximab combination after failure of the cisplatin regimen. We observed a necrosis of the inguinal lymph nodes and a reduction of 18F-fluorodeoxyglucose uptake at PET/CT scan. Only mild mucositis and skin toxicity had been detected. Our case report, the first in the literature, shows that this combination is active and well tolerated in penile squamous cell carcinoma.

Prognostic risk stratification derived from individual patient level data for men with advanced penile squamous cell carcinoma receiving first-line systemic therapy

BACKGROUND Prognostic factors in men with penile squamous cell carcinoma (PSCC) receiving systemic therapy are unknown. A prognostic classification system in this disease may facilitate interpretation of outcomes and guide rational drug development. We performed a retrospective analysis to identify prognostic factors in men with PSCC receiving first-line systemic therapy for advanced disease. PATIENTS AND METHODS Individual patient level data were obtained from 13 institutions to study prognostic factors in the context of first-line systemic therapy for advanced PSCC. Cox proportional hazards regression analysis was conducted to examine the prognostic effect of these candidate factors on progression-free survival (PFS) and overall survival (OS): age, stage, hemoglobin, neutrophil count, lymphocyte count, albumin, site of metastasis (visceral or nonvisceral), smoking, circumcision, regimen, ECOG performance status (PS), lymphovascular invasion, precancerous lesion, and surgery following chemotherapy. The effect of different treatments was then evaluated adjusting for factors in the prognostic model. RESULTS The study included 140 eligible men. Mean age across all men was 57.0 years. Among them, 8.6%, 21.4%, and 70.0% of patients had stage 2, 3, and 4 diseases, respectively; 40.7% had ECOG PS ≥ 1, 47.4% had visceral metastases, and 73.6% received cisplatin-based chemotherapy. The multivariate model of poor prognostic factors included visceral metastases (P<0.001) and ECOG PS ≥ 1 (P<0.001) for both PFS and OS. A risk stratification model constructed with 0, 1, and both poor prognostic factors was internally validated and demonstrated moderate discriminatory ability (c-statistic of 0.657 and 0.677 for OS and PFS, respectively). The median OS for the entire population was 9 months. Median OS was not reached, 8, and 7 months for those with 0, 1, and both risk factors, respectively. Cisplatin-based regimens were associated with better OS (P = 0.017) but not PFS (P = 0.37) compared with noncisplatin-based regimens after adjusting for the 2 prognostic factors. CONCLUSIONS In men with advanced PSCC receiving first-line systemic therapy, visceral metastases and ECOG PS ≥ 1 were poor prognostic factors. A prognostic model including these factors exhibited moderate discriminatory ability for outcomes and warrants external validation. Patients receiving cisplatin-based regimens exhibited better outcomes compared with noncisplatin-based regimens after adjusting for prognostic factors.

Peg-filgrastim and cabazitaxel in prostate cancer patients.

To determine the impact of prophylaxis with granulocyte-colony stimulating growth factor (G-CSF) on the risk of febrile neutropenia in a cohort of patients enrolled at the University Federico II of Naples and treated with cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC). We carried out a retrospective review of prospectively collected data of patients enrolled at our institution in a compassionate-use programme with cabazitaxel, aimed at providing early access to the drug before its commercial availability in mCRPC patients. Besides baseline clinical and demographic characteristics, data on treatment efficacy and toxicity, as well as those on the use of G-CSF per patient per cycle were extracted. Progression-free survival and overall survival were calculated using the Kaplan–Meier method. Fisher’s exact test was used to explore a relationship between a single event of grade 3 or more neutropenia or febrile neutropenia and previous use of G-CSF. Univariate analysis was carried out to evaluate predictors of grade 3 or more neutropenia and/or febrile neutropenia. Of 34 patients enrolled at our institution from December 2010 to December 2011, 32 had received at least one dose of cabazitaxel and were included in the analysis. Patients received a median of 10 cabazitaxel cycles. Grade 3 or more neutropenia was common, occurring in 64.5% of patients. Three patients (9.3%) developed febrile neutropenia. Twenty-seven patients received prophylaxis with G-CSF during at least one cycle using peg-filgrastim. The risk of grade 3 or more neutropenia and/or febrile neutropenia per patient and per cycle was seven times lower when G-CSF was used. Baseline neutrophil count of less than 4570/mm3 was the strongest predictor of grade 3 or more neutropenia and/or febrile neutropenia. No toxic death was reported. Only one patient discontinued cabazitaxel because of an adverse event. Our analysis suggests that prophylaxis with peg-filgrastim may considerably reduce the incidence of grade 3 or more neutropenia and, possibly, of febrile neutropenia in mCRPC patients treated with cabazitaxel. Further analyses involving a larger population are warranted to confirm our results.

Carboplatin plus etoposide in heavily pretreated castration-resistant prostate cancer patients

AIMS Carboplatin plus etoposide has modest efficacy in docetaxel-pretreated castration-resistant prostate cancer patients. We hypothesized that carboplatin-etoposide could still exert some therapeutic activity after docetaxel, cabazitaxel and either abiraterone or enzalutamide. PATIENTS & METHODS We enrolled 15 patients in the first step of a Phase II trial. The target sample size is 46 patients. The primary end point of the study was progression-free survival after 12 weeks. RESULTS The median progression-free survival was 11 weeks (range: 8-18), while median overall survival was 18 weeks (range: 12-26). Of seven patients with measurable disease, two had a partial response, two showed stable disease and the remaining three had progressive disease as the best radiological response. Five patients were considered progression-free after 12 weeks, prompting continuation of the trial. CONCLUSION Our preliminary findings support the hypothesis that carboplatin plus etoposide may yield some clinical benefit in a population of patients who failed all currently approved therapeutic options for prostate cancer.