Giovannella Palmieri

Phase II Study of Sorafenib in Patients With Sunitinib-Refractory Metastatic Renal Cell Cancer

PURPOSE No previous prospective trials have been reported with sorafenib in patients with sunitinib-refractory metastatic renal cell cancer (MRCC). We conducted a multicenter study to determine the activity and tolerability of sorafenib as second-line therapy after sunitinib progression in MRCC. PATIENTS AND METHODS Between January 2006 and September 2008, 52 patients were enrolled onto this single-arm phase II study. All patients received sorafenib 400 mg orally twice a day until disease progression or intolerable toxicity. The primary end point was objective response rate (complete or partial response) evaluated every 8 weeks by use of the Response Evaluation Criteria in Solid Tumors; secondary end points were toxicity, time to progression (TTP), and overall survival (OS). RESULTS All patients were included in response and safety analyses. Partial responses were observed in 9.6% of patients (five of 52 patients; 95% CI, 5% to 17%) after two cycles. Grade 1 to 2 fatigue, diarrhea, nausea/vomiting, rash, and neutropenia were the most common side effects, noted in 16 (30.8%), 19 (36.5%), 20 (38.5%), 19 (36.5%), and 20 patients (38.5%), respectively. The most common grade 3 toxicity was diarrhea, noted in six patients (11.5%). Median TTP was 16 weeks (range, 8 to 40 weeks), and median OS was 32 weeks (range, 16 to 64 weeks). CONCLUSION Although well tolerated, sorafenib shows limited efficacy in sunitinib-refractory MRCC. Further randomized trials comparing sorafenib with other drugs that target different biologic pathways are needed to define the best second-line treatment option in these patients.

Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer.

We have evaluated the activity and safety of gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with docetaxel as first-line treatment of women with metastatic breast cancer (MBC). In total, 41 patients with MBC were enrolled in a first-line combination therapy study with oral gefitinib (250 mg day−1) and intravenous docetaxel (75 mg m−2, the first 14 patients; or 100 mg m−2, the following 27 patients, on day 1 of a 3-week cycle). Out of 41 patients, 38 received at least one cycle of therapy. There were no differences in activity or tolerability between the two docetaxel doses. G3/4 toxicities were neutropenia (49%), diarrhoea (10%), acne-like rash (5%), and anaemia (2%). Complete plus partial responses (CR+PR) were observed in 22 out of 41 patients with a 54% response rate (95% confidence interval (CI) 45–75%). The 22 patients that achieved a response following six cycles of docetaxel plus gefitinib continued gefitinib monotherapy (median duration, 24 weeks; range, 2–108+ weeks). Two patients with PR following combination therapy achieved a CR during gefitinib monotherapy. Complete plus partial responses correlated with oestrogen receptor (ER) status, since they occurred in 19 out of 27 (70%) patients with ER-positive tumours as compared to three out of 14 (21%) patients with ER-negative tumours (P=0.01).

Phase II study of docetaxel re-treatment in docetaxel-pretreated castration-resistant prostate cancer

Study Type – Therapy (cohort)
Level of Evidence 2b

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.

Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET

Radioactive iodine is a crucial tool for treatment of differentiated thyroid cancer (DTC). In 5% of cases, DTCs lose I‐131 avidity and assume an aggressive behaviour. Treatment options for iodine‐refractory DTC are limited. We report the experience of off‐label use of the tyrosine kinase inhibitor sorafenib for treatment of advanced iodine‐refractory DTC.

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.

Cetuximab is an active treatment of metastatic and chemorefractory thymoma

Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. A rationale-based therapeutic approach targeting a key pathway should represent the ideal solution in a neoplasm that can over-express Epidermal Growth Factor Receptor (EGFR) in the epithelial component. On the basis of these considerations, two patients with metastatic heavily pretreated disease were evaluated for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment with the monoclonal antibody cetuximab which targets EGFR. A strong EGFR expression was revealed by immunohistochemistry in the two cases considered, thus the patients received cetuximab and reported a partial response as assessed by Computed Tomography (CT), Positron Emission Tomography (PET) and fused PET-CT after three months of therapy. Therefore, both patients are still on therapy. This preliminary experience suggests that cetuximab may be a useful therapeutic choice in advanced pre-treated thymic tumors.

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.

Ultra-low-dose interleukin-2 in unresectable hepatocellular carcinoma

At present, no effective therapy is available for hepatocellular carcinoma, when local treatments have failed. We reported the results obtained with prolonged, ultra-low-dose (1 MIU/d until progression), subcutaneous interleukin-2 (IL-2) in a series of 18 consecutive patients (14 men and 4 women, median age 66 years, range 49–82 years) with advanced, histologically proven HCC on liver cirrhosis. During a median follow-up time of 19.5 months, two complete responses (11.1%), lasting 35 and 46 months, respectively, and one partial response (5.5%) were recorded (overall response rate: 16.6%; 95% CI: 0–33.8%). Thirteen patients (72.3%; 95% CI: 61.6–82.7) had stable disease lasting at least 4 months; 1 of these patients obtained a complete response on lung metastases. Median time to progression was 15.3 months (95% CI: 10–33). Median overall survival was 24.5 months (95% CI: 12–43). Two patients (11.1%) progressed during therapy. Toxicity was only local (usually pain and pomphus in the site of injection). Low-dose IL-2 can be considered an active and well-tolerated treatment for unresectable hepatocellular carcinoma. Future studies on large numbers of patients are necessary to confirm these results.