Medline ® Abstracts for References 24-29
Sorafenib in advanced clear-cell renal-cell carcinoma.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group
N Engl J Med. 2007;356(2):125.
BACKGROUND: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of sorafenib, a multikinase inhibitor of tumor-cell proliferation and angiogenesis, in patients with advanced clear-cell renal-cell carcinoma.
METHODS: From November 2003 to March 2005, we randomly assigned 903 patients with renal-cell carcinoma that was resistant to standard therapy to receive either continuous treatment with oral sorafenib (at a dose of 400 mg twice daily) or placebo; 451 patients received sorafenib and 452 received placebo. The primary end point was overall survival. A single planned analysis of progression-free survival in January 2005 showed a statistically significant benefit of sorafenib over placebo. Consequently, crossover was permitted from placebo to sorafenib, beginning in May 2005.
RESULTS: At the January 2005 cutoff, the median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01). The first interim analysis of overall survival in May 2005 showed that sorafenib reduced the risk of death, as compared with placebo (hazard ratio, 0.72; 95% CI, 0.54 to 0.94; P=0.02), although this benefit was not statistically significant according to the O'Brien-Fleming threshold. Partial responses were reported as the best response in 10% of patients receiving sorafenib and in 2% of those receiving placebo (P<0.001). Diarrhea, rash, fatigue, and hand-foot skin reactions were the most common adverse events associated with sorafenib. Hypertension and cardiac ischemia were rare serious adverse events that were more common in patients receiving sorafenib than in those receiving placebo.
CONCLUSIONS: As compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear-cell renal-cell carcinoma in whom previous therapy has failed; however, treatment is associated with increased toxic effects. (ClinicalTrials.gov number, NCT00073307 [ClinicalTrials.gov].).
Department of Medicine, Institut Gustave Roussy, Villejuif, France. email@example.com
Sorafenib in advanced hepatocellular carcinoma.
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group
N Engl J Med. 2008;359(4):378.
BACKGROUND: No effective systemic therapy exists for patients with advanced hepatocellular carcinoma. A preliminary study suggested that sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor, the platelet-derived growth factor receptor, and Raf may be effective in hepatocellular carcinoma.
METHODS: In this multicenter, phase 3, double-blind, placebo-controlled trial, we randomly assigned 602 patients with advanced hepatocellular carcinoma who had not received previous systemic treatment to receive either sorafenib (at a dose of 400 mg twice daily) or placebo. Primary outcomes were overall survival and the time to symptomatic progression. Secondary outcomes included the time to radiologic progression and safety.
RESULTS: At the second planned interimanalysis, 321 deaths had occurred, and the study was stopped. Median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio in the sorafenib group, 0.69; 95% confidence interval, 0.55 to 0.87; P<0.001). There was no significant difference between the two groups in the median time to symptomatic progression (4.1 months vs. 4.9 months, respectively, P=0.77). The median time to radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo group (P<0.001). Seven patients in the sorafenib group (2%) and two patients in the placebo group (1%) had a partial response; no patients had a complete response. Diarrhea, weight loss, hand-foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group.
CONCLUSIONS: In patients with advanced hepatocellular carcinoma, median survival and the time to radiologic progression were nearly 3 months longer for patients treated with sorafenib than for those given placebo. (ClinicalTrials.gov number, NCT00105443.)
Barcelona Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigaciones en Red de Enfermedades Hepáticas y Digestivas Hospital Clínic Barcelona, Barcelona. firstname.lastname@example.org
Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.
Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M, Desai AA, Patnaik A, Xiong HQ, Rowinsky E, Abbruzzese JL, Xia C, Simantov R, Schwartz B, O'Dwyer PJ
J Clin Oncol. 2006;24(16):2505. Epub 2006 Apr 24.
PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma.
PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with>or = 25% tumor shrinkage continued open-label sorafenib; patients with>or = 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib.
RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of>or = 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity.
CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.
University of Chicago, Chicago, IL 60637, USA. email@example.com
Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor.
Autier J, Escudier B, Wechsler J, Spatz A, Robert C
Arch Dermatol. 2008;144(7):886.
OBJECTIVES: To provide an accurate description and to evaluate the incidence and severity of cutaneous reactions induced by sorafenib tosylate, a new oral multikinase inhibitor.
DESIGN: Double-blind, prospective dermatologic substudy performed on all consecutive patients included in our center in a large phase 3 trial.
SETTING: Institutional practice at the Gustave Roussy Institute.
PATIENTS: Eighty-five patients with renal cell cancer treated between November 1, 2003, and February 28, 2005. Interventions Patients were randomized to receive either sorafenib (n = 43) or placebo (n = 42). Dermatologic examination was performed before treatment, every 3 weeks during the first 4 cycles, and every 4 weeks thereafter.
MAIN OUTCOME MEASURES: Incidence and severity of cutaneous reactions to sorafenib.
RESULTS: Thirty-nine patients (91%) experienced at least 1 cutaneous reaction in the sorafenib group vs 3 (7%) in the placebo group. A hand-foot skin reaction that appeared to be clinically distinct from the well-known chemotherapy-induced hand-foot syndrome was observed in 26 patients receiving sorafenib (60%). Reversible grade 3 hand-foot skin reaction was documented in 2 patients receiving sorafenib and led to a dose reduction. Other cutaneous reactions were facial erythema, scalp dysesthesia, alopecia, and subungual splinter hemorrhages.
CONCLUSIONS: Sorafenib induces frequent cutaneous adverse events, some of which may lead to a dose reduction. Close collaboration between oncologists and dermatologists is needed to improve both the characterization and the management of these side effects. Appropriate patient education before the initiation of therapy and the introduction of early symptomatic measures may improve management.
Dermatology Unit, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ
Lancet. 2011 Dec;378(9807):1931-9. Epub 2011 Nov 4.
BACKGROUND: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer.
METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392.
FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm.
INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma.
FUNDING: Pfizer Inc.
Cleveland Clinic Taussig Cancer Institute, Main Campus, Euclid Avenue, Cleveland, OH 44195, USA. firstname.lastname@example.org
Meta-analysis of dermatological toxicities associated with sorafenib.
Zhang L, Zhou Q, Ma L, Wu Z, Wang Y
Clin Exp Dermatol. 2011 Jun;36(4):344-50. Epub 2011 Apr 20.
A meta-analysis was performed to determine the type, incidence and risks of dermatological toxicities associated with the multikinase inhibitor sorafenib. A literature search was performed using the electronic databases PubMed and EMBASE, and conference abstracts published by the American Society of Clinical Oncology. Eligible studies included prospective phase II or III clinical trials, and expanded-access programmes (i.e. outside a clinical trial) of patients with solid tumours assigned sorafenib at a starting dose of 400 mg twice daily. The overall incidences and risk ratios of dermatological toxicities associated with sorafenib were analysed. For patients assigned sorafenib, the overall incidence of all-grade rash/desquamation was 35.4% (95% CI 0.29-0.43), hand-foot skin reaction (HFSR) 39.0% (95% CI 0.32-0.47), alopecia 25.5% (95% CI 0.18-0.35), pruritus 14.0% (95% CI 0.10-0.20) and dry skin 14.1% (95% CI 0.10-0.20). High-grade rash/desquamation events occurred in 5.0% (95% CI 0.04-0.07), HFSR in 9.0% (95% CI 0.082-0.098), alopecia in 4/1793, pruritus in 2/1265 and dry skin in 0/1689 of patients assigned sorafenib. Meta-analysis of risk ratio showed that sorafenib was associated with a significantly increased risk of rash/desquamation [risk ratio (RR) 2.73; 95% CI 1.66-4.49)], HFSR (RR 7.50; 95% CI 3.90-14.40) and alopecia (RR 7.55; 95% CI 5.26-10.84) in patients with solidtumours, but risk of pruritus (RR 1.80; 95% CI 0.77-4.22) or dry skin (RR 2.18; 95% CI 0.88-5.40) was not increased. In conclusion, the most frequent dermatological toxicities associated with sorafenib were HFSR, rash/desquamation, alopecia, pruritus and dry skin. There was a significantly increased risk of HFSR, rash/desquamation and alopecia with sorafenib compared with placebo. Skin toxicities were mainly mild or moderate in severity. Appropriate prevention and management are recommended.
Department of Oncology Tianjin Lung Cancer Center and Institute, Tianjin Medical University General Hospital, Tianjin, China.