Anti-angiogenic drugs currently in Phase II clinical trials for gynecological cancer treatment

Introduction: Numerous female patients suffer from gynecological cancers every year. When it comes to recurrent or chemoresistant cancers, there are limited treatment options. For decades, much enthusiasm has been shown for novel therapeutic strategies for cancers, and anti-angiogenesis agents appear to be a potential option. Since several promising angiogenesis inhibitors for certain cancers have been approved by Food and Drug Administration, more and more anti-angiogenic drugs are put into clinical trials.

Areas covered: In this review, the anti-angiogenic agents in Phase II clinical trials for gynecological cancer treatment are highlighted. This review mainly focuses on 5-year reports on angiogenesis inhibitors concerning ovarian cancer, cervical cancer, uterine leiomysarcoma and endometrial cancer. Inhibitors reviewed in this paper include bevacizumab, volociximab, aflibercept, temsirolimus, enzastaurin, trebananib, sunitinib, imatinib, pazopanib, sorafenib and nintedanib.

Expert opinion: These anti-angiogenic drugs while used either alone or in combination with chemotherapy, presented mixed results in treating gynecological cancers. The real challenge is how to take best advantage of the anti-angiogenesis hypothesis for therapeutic benefit. Much remains to be done before these molecules work efficaciously in treating gynecological cancer.     

Cost implications of IV versus oral anti-angiogenesis therapies in patients with advanced renal cell carcinoma: retrospective claims database analysis*

ABSTRACT

Objective: Angiogenesis inhibitors (AI) are promising novel treatments for patients with renal cell carcinoma (RCC). However, IV therapy may impose infection risk from IV catheters, and will include increased costs due to administration and transportation costs. This study evaluated the incremental costs associated with IV administration of selected AI therapies (bevacizumab off-label) compared to oral therapies (sunitinib or sorafenib) for the treatment of RCC.

Methods: Patients with ≥2 RCC claims (ICD-9: 189.0, 198.0) were identified from a US commercial health insurance claims database from 1/2004 to 12/2007. Patients receiving bevacizumab (n?=?109) were matched 1:1 to patients receiving sorafenib or sunitinib, and observed from their first AI therapy claim until the last treatment date. AI, inpatient, outpatient and pharmacy costs were calculated on a per-patient per-month (PPPM) basis over the treatment period. Costs were compared between the IV AI group and each separate oral AI group using multivariate Tobit regressions for each category separately, adjusting for demographic and baseline clinical characteristics. This study assessed costs of treatment and did not evaluate the cost-effectiveness of AIs.

Results: Mean total medical costs were $13?351, $6998, and $8213 PPPM for bevacizumab, sorafenib, and sunitinib, respectively (p?<0.05 for equality). Adjusted incremental total cost for the bevacizumab group was $4951 PPPM compared to sorafenib and $4610 PPPM compared to sunitinib (both p?<?0.05). Bevacizumab patients incurred incremental PPPM outpatient services cost compared to sorafenib and sunitinib of $2772 and $2548, respectively (both p?<?0.05).

Conclusions: Assuming median progression-free survival of 8.5 months as shown for bevacizumab (Bukowski, et al., J Clin Oncol 2007), the incremental costs would be estimated at $39?188–42?080 per patient compared to those treated with sunitinib or sorafenib. Assuming similar efficacies, oral AI therapies may result in cost savings to patients and healthcare payers over IV therapies.     

Systemic therapy for metastatic renal cell carcinoma in treatment naïve patients: a risk-based approach

Importance of the field: Kidney cancer is the ninth most common cancer in the USA, with an annual incidence of approximately 55,000 cases per year. Over 13,000 patients are estimated to die from this disease annually. Cloning of the VHL gene, recognition of the associated abnormalities in sporadic clear-cell carcinoma, and its role as a regulator of the hypoxic response, were important milestones in our understanding of renal-cell carcinoma (RCC) biology and the recognition of the vascular endothelial growth factor (VEGF) dependency of RCC. A variety of clinical features, including histologic features, prognostic factors, and patient history of comorbid illness, provide the framework in which the results of recent clinical trials and regulatory approvals of these agents are utilized to develop treatment recommendations for the largest metastatic patient RCC group, the therapy naïve individual.

Areas covered in this review: The rationale for use of VEGF-targeted therapy in advanced RCC patients and the recently developed treatment options for these individuals are reviewed. Regulatory approval of sorafenib for the treatment of metastatic RCC (mRCC), was followed by the approval of sunitinib, temsirolimus, bevacizumab plus interferon (IFNα), everolimus, and – most recently – pazopanib. These licences were granted from late 2005 through late 2009, a very short span of 4 years. In treatment-naïve mRCC patients, sunitinib, sorafenib, pazopanib, bevacizumab + IFNα, and temsirolimus were approved by the Food and Drug Administration (FDA) and/or the European Medicines Agency (EMEA). The clinical trials and data supporting these approvals are reviewed.

What will the reader gain: This review examines these developments and provides the reader an overview and understanding of available current systemic therapy options for treatment-naïve mRCC patients.

Take home message: As multiple treatment options are now available for treatment-naïve mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection. These features include prior treatment status, histologic subtype, and prognostic group. Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials.     

Pazopanib for the treatment of renal cancer

Introduction: Dramatic advances in the care of patients with advanced renal cell carcinoma (RCC) have occurred over the last 10 years. Insights into the molecular pathogenesis of this disease have elucidated the importance of signaling cascades related to angiogenesis in the management of RCC. Pazopanib is a novel, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3; platelet-derived growth factor receptors (PDGFR)-α and -β; and c-kit tyrosine kinases. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in the class of VEGF signaling pathway inhibitors.

Areas covered: This review discusses the scientific rationale for the development of pazopanib, as well as the preclinical and clinical trials that led to the approval of pazopanib for patients with advanced RCC. The most recent information, including data from the 2010 meeting of the American Society of Clinical Oncology and the design of ongoing Phase III trials, is discussed. Finally, an algorithm utilizing level I evidence for the treatment of patients with this disease is proposed.

Expert opinion: The treatment of metastatic RCC has changed dramatically over the last 5 years. Six novel agents – sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab (used in combination with interferon), and pazopanib (Votrient) – have been approved for the treatment of metastatic RCC. The clinical data to date clearly place pazopanib among the most active of the targeted therapies.     

Targeted therapy and hand–foot skin reaction in advanced renal cell carcinoma

Importance of the field: Targeted therapy has significantly prolonged the survival of patients with advanced renal cell carcinoma (RCC). As first-line treatment, sunitinib, temsirolimus and bevacizumab plus IFN-α are demonstrated to prolong progression-free survival and/or overall survival. As second-line treatment, sorafenib was active mainly for patients in whom cytokine therapy failed. Recently, second-line treatment with everolimus has been shown to benefit patients progressing through tyrosine kinase inhibitors. Meanwhile, FDA has just approved pazopanib for the treatment of patients with advanced RCC. Various toxicities were associated with these agents. These toxicities were generally well tolerated. However, a high frequency of severe skin and bone marrow toxicities has been reported in Asian countries.

Areas covered in this review: We have reviewed the literature of current targeted therapeutic agents and hand–foot skin reaction (HFSR) in advanced RCC available in MEDLINE and meeting reports of ASCO, ECCO-ESMO and the 2009 Genitourinary Cancers Symposium.

What the reader will gain: Readers will know of the efficacy and safety, including HFSR, of current targeted therapy.

Take home message: Careful monitoring and appropriate management of the toxicities, especially HFSR, are needed.     

First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis

Objectives: To conduct a systematic review and network meta-analysis (NMA) to assess effectiveness of first-line treatments for advanced renal cell carcinoma (RCC).

Methods: Database searches were conducted to identify randomized controlled trials (RCTs) reporting results for eligible treatments. A fixed-effect Bayesian NMA was conducted to assess the relative effectiveness of treatments, with progression-free survival (PFS) reported as hazard ratios (HRs) and 95% credible intervals (CrIs).

Results: Eleven unique RCTs were suitable for inclusion in the NMA. In the base case, in terms of PFS, sunitinib was superior compared with bevacizumab + IFN-α (HR = 0.79, 95% CrI: 0.64 – 0.96), everolimus (HR = 0.70, 95% CrI: 0.56 – 0.87), sorafenib (HR = 0.56, 95% CrI: 0.40 – 0.77) and temsirolimus + bevacizumab (HR = 0.74, 95% CrI: 0.56 – 0.96). Although, the point values for the mean and median HRs were < 1.0, there was no significant difference in PFS between sunitinib and axitinib, pazopanib or tivozanib. Although sensitivity analyses impacted the results of the NMA, no treatment was significantly more efficacious than sunitinib.

Conclusion: Results from this analysis suggest that there is no treatment superior to the current benchmark treatment, sunitinib, in the management of advanced RCC in the first-line setting.     

Emerging therapies: angiogenesis inhibitors for ovarian cancer

Introduction: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ～ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC.

Areas covered: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib.

Expert opinion: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.     

Targeting angiogenesis in endometrial cancer - new agents for tailored treatments

Introduction: Endometrial carcinoma represents the most frequent gynecologic tumor in developed countries. The majority of women presents with low-grade tumors but a significant subset of women experience recurrence and do not survive their disease. Patients with stage III/ IV or recurrent endometrial cancer have a poor prognosis. Identification of active and tolerable new targeted agents versus specific molecular targets is a priority objective. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer and in particular endometrial cancer.

Areas covered: In this review, the authors highlight the main angiogenetic molecular pathways and the anti-angiogenic agents in Phase II clinical trials for endometrial cancer treatment. The authors focus on reports from recent years on angiogenesis inhibitors used in endometrial cancer, including anti- vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab and aflibercept), mammalian target of rapamycin inhibitors (mTORi) (everolimus, temsirolimus and ridaforolimus), PI3 K inhibitors (BKM120), tyrosine kinase inhibitors (brivanib, sunitinib, dovitinib and nintedanib) and thalidomide.

Expert opinion: These anti-angiogenic drugs, while used either alone or in combination with chemotherapy, have presented mixed results in treating endometrial cancer patients. Challenges for the future include the identification of new pathways, early identification and overcoming resistance and the use of these molecules in combination with old and new chemotherapeutic and targeted agents.     

Sunitinib in solid tumors

Background: Until recently, few treatments were available for renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST). Several targeted agents inhibiting key pathogenetic pathways have since been developed for RCC (sunitinib, sorafenib, bevacizumab, temsirolimus, everolimus) and GIST (imatinib, sunitinib). Sunitinib is a multi-kinase inhibitor of VEGFR-2, PDGFR (α,β), FLT-3, KIT, CSF-1 and RET. Objective: To summarize the literature regarding the structure, pharmacokinetics, pharmacodynamics, toxicity and current clinical use of sunitinib. Other potential roles for this drug in RCC, GIST and other tumor types will be discussed. Methods: A literature search identified relevant (pre)clinical studies of sunitinib and other relevant agents. Results/conclusions: Sunitinib revolutionized the management of advanced RCC and GIST. With the realization that cross-resistance between targeted agents is incomplete, evolving strategies include sequential treatment, concurrent treatment, and biomarker development. Sunitinib also shows promise in several other tumor types that lack therapeutic options. What remains less clear is its role in tumors that are not heavily dependent on a central pathogenetic pathway, especially if effective cytotoxic therapies exist. Future clinical trials will clarify whether there is a role for sunitinib in these tumors, possibly in combination with cytotoxic agents.     

Pooled analysis of GI tolerability of 21 randomized controlled trials of celecoxib and nonselective NSAIDs

ABSTRACT

Objective: To compare the gastrointestinal (GI) tolerability of celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) at approved doses in patients with common musculoskeletal conditions.

Research design and methods: This was a retrospective, pooled analysis of studies selected from the Pfizer Corporate Clinical Trials Registry. Study selection criteria were: (1) Data available as of October 31, 2004; (2) Randomized, parallel-group study design and planned treatment duration of ≥?2 weeks; (3) At least one nonselective NSAID (naproxen, ibuprofen, or diclofenac) as a comparator; (4) At least one arm with 200?mg or 400?mg celecoxib per day; (5) Patients with osteoarthritis (OA), adult rheumatoid arthritis (RA), or ankylosing spondylitis (AS).

Data were pooled by treatment and by subject from the safety analysis population of each included study. Joint primary end points were the combined incidence of tolerability-related GI adverse events (AEs) (abdominal pain, dyspepsia, nausea, diarrhea, and flatulence), and time to study discontinuation due to any GI?AE.

Results: In all, 21 studies met the selection criteria. Across the safety analysis populations of the included studies, 7797 patients received celecoxib total daily dose 200?mg/day, 6653 received celecoxib total daily dose 400?mg/day, 2953 received naproxen, 499 received ibuprofen, and 5643 received diclofenac. Tolerability-related GI AEs were reported by significantly fewer celecoxib-treated patients (16.0%) than by those treated with naproxen (24.3%), ibuprofen (24.2%), or diclofenac (19.9%) (p?<?0.0001 vs. each comparator). Time to study discontinuation due to any GI?AE was significantly longer for celecoxib than for naproxen (p?<?0.0001), ibuprofen (p?=?0.002), or diclofenac (p?=?0.048). In the RA subpopulation (n?=?2857), there was no significant difference between the celecoxib and naproxen or ibuprofen groups in incidence of tolerability-related GI AEs and GI AEs.

Limitations: The limitations are inherent to the retrospective analysis design.

Conclusions: In this pooled analysis of celecoxib at approved doses in OA, RA, and AS, fewer celecoxib-treated patients in the overall population had tolerability-related GI AEs than patients treated with naproxen, ibuprofen, or diclofenac. In addition, celecoxib-treated patients had a significantly longer time to study discontinuation due to GI AEs.     

Safety of monoclonal antibodies and related therapeutic proteins for the treatment of neovascular macular degeneration: addressing outstanding issues

Introduction: The vascular endothelial growth factor (VEGF) inhibitors most widely used to treat neovascular age-dependent macular degeneration (nAMD) are different proteins with structural features potentially relevant to adverse effects (AEs). Two of these are also established in cancer therapy (with higher dosages and AEs). The importance of ocular AE and extraocular activities is still a subject of controversy and ongoing research.

Areas covered: Potential risks of intraocular VEGF inhibition based on prospective studies, in vitro investigations, pharmacokinetics, and hints from anti-cancer treatment.

Expert opinion: nAMD is a frequently observed chronic clinical condition severely affecting the visual function of elderly persons. Intravitreal injection of VEGF-inactivating proteins is highly effective to prevent loss of vision. Anti-VEGF therapy is well tolerated, and low rates of ocular and systemic AEs in smaller trials suggest a very high benefit/risk ratio. The proteins established in nAMD therapy show similar efficacies. In the controversy over the off-label use of bevacizumab purely on grounds of much lower cost, the small, but potentially relevant differences between the available drugs are easily either dramatized (by pharmaceutical companies) or trivialized (by health insurances) and even political interference is involved. Facing the lack of a convincing body of evidence regarding safety, further long-term study results seem necessary.     

Long-term safety and tolerability of entecavir in patients with chronic hepatitis B in the rollover study ETV-901

Objective: To review long-term safety data from the rollover study ETV-901, focusing on adverse events (AEs) with a potential nucleos(t)ide association.

Methods: The open-label study ETV-901 (AI463901) assessed the safety of entecavir in chronic hepatitis B patients who received entecavir, lamivudine or adefovir monotherapy in previous entecavir Phase II/III studies. Long-term cumulative safety results are based on reported AEs, regardless of causal relationship.

Results: Median exposure to entecavir in study ETV-901 was 184 weeks. Commonly reported AEs (≥ 10%) were upper respiratory tract infection, headache and nasopharyngitis. Most AEs were mild to moderate; 203 (19%) patients reported grade 3 – 4 AEs, with 45 (4%) considered related to entecavir. There were 14 (1%) discontinuations due to AEs. On-treatment alanine aminotransferase (ALT) flares were reported in 32 (3%) patients and were associated with a reduction in hepatitis B virus DNA of more than 2 log₁₀ copies/ml in 25/32 patients. AEs potentially associated with nucleos(t)ide analogs were infrequent, the most common being myalgia (n = 54; 5%) and neuropathy-related AEs (hypoparesthesia and hyperparesthesia, polyneuropathy; n = 42; 4%).

Conclusions: Long-term administration of entecavir was associated with low rates of serious AEs, discontinuations due to AEs and ALT flares. AEs potentially associated with nucleos(t)ide use occurred at low rates.     

Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization

Aim: To evaluate the effects of sunitinib (0.5?mg/ml) and bevacizumab (5?mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV).

Methods: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups:

Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5?mg/ml sunitinib eyedrop was administered twice daily for two weeks (n?=?10).

Group 2 (bevacizumab): After silver nitrate application to the cornea, 5?mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n?=?10).

Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n?=?10).

Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n?=?10).

After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15?b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR-423) were evaluated by real-time PCR.

Results: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15?b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups.

Conclusion: Topical application of bevacizumab (5?mg/ml) and sunitinib (0.5?mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study.     

Pazopanib,a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.     

Cabazitaxel for metastatic castration-resistant prostate cancer: safety data from the Spanish expanded access program

Background: Based on the TROPIC study results, cabazitaxel was approved for the management of metastatic castration-resistant prostate cancer (mCRPC) progressing on or after docetaxel.

Methods: This multi-centre program provided early access to cabazitaxel to patients with mCRPC before its commercialization. Safety data from 153 Spanish patients receiving cabazitaxel 25 mg/m² i.v. Q3W, plus oral prednisone/prednisolone 10 mg daily, are reported.

Results: Median age of patients was 70 years (26.8% ≥ 75 years), 94.1 and 26.8% had bone and visceral metastasis, respectively. Most had an Eastern Cooperative Oncology Group ≤ 1 (88.9%) and had received a median of 8.0 cycles of last docetaxel treatment. The median of cabazitaxel cycles and cumulative dose were 6.0 (Interquartile range [IQR]: 4.0; 8.0) and 148.9 (IQR: 98.2; 201.4) mg/m², respectively. Adverse events (AEs) possibly related to cabazitaxel occurred in 143 (93.5%) patients. The most frequent grade ≥ 3 AEs were neutropenia (n = 25, 16.3%) and asthenia (n = 17, 11.1%). Febrile neutropenia and grade ≥ 3 diarrhea occurred in 5.2% of the patients each. There were five (3.3%) possibly treatment-related deaths, mainly infection-related. G-CSFs were used in 114 (74.5%) patients, generally as prophylaxis (n = 107; 69.9%). Grade ≥ 3 peripheral neuropathy and nail disorders were uncommon.

Conclusions: Cabazitaxel administration, in a real-world setting, is tolerated by Spanish patients with mCRPC, and the AEs are manageable.     

Targeted therapy of renal cell cancer

Rapid development of treatment strategies for renal cell cancer (RCC) has occurred in recent years. Elucidation of the crucial role of the Von Hippel-Lindau (VHL) tumor suppressor gene in upregulating growth factors associated with angiogenesis has provided new insight into RCC biology and has identified specific targets for novel therapeutic strategies. For almost two decades, cytokine-based immunotherapy has remained a treatment of choice in advanced RCC patients. However, it has provided only modest improvement in clinical outcome and has been associated with severe toxicity. With the advent of novel therapies directly targeting the VEGF molecule or VEGF receptor signal transduction pathway, the clinical outcome in high-risk, advanced RCC has significantly improved. In phase III clinical trials, novel targeted agents - temsirolimus, sorafenib, sunitinib and bevacizumab - significantly prolonged progression-free survival of patients with metastatic RCC and, crucially, temsirolimus also prolonged overall survival in patients with high-risk disease. Despite the obvious clinical efficacy of novel targeted therapies in the treatment of RCC, many unanswered questions still remain; in particular, the efficacy of targeted agents in patients with low-risk RCC, the optimal sequence and combination of therapies for first-, second-, or third-line treatment, and the efficacy of this strategy in adjuvant settings.     

Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience

ABSTRACT

Background: Carmustine (1,3-bis [2-chloroethyl]-1-nitrosourea, or BCNU) wafers are approved for recurrent glioblastoma and newly diagnosed malignant glioma (MG). Based on considerable clinical experience and use in multimodal regimens, the safety of BCNU wafers needs a re-evaluation.

Scope: A review of literature from 1996 to February 2008 was conducted on the safety of BCNU wafer in MG patients using search criteria in Medline, EMBASE, and BIOSIS. Abstracts from relevant US and European meetings were also evaluated. Three Phase III (two were pivotal) and 26 non-Phase III studies met inclusion criteria. Overall incidence was estimated for each adverse event (AE), and data from individual studies were summarised as median (range) rates. Comparisons were based on consistent similarities or differences across overall incidence, median rate and range.

Findings: BCNU wafer group AE rates from the two pivotal Phase III trials ranged from 4–23% for cerebral oedema, 4–9% for intracranial hypertension, 14–16% for healing abnormalities, 5% for CSF leaks, 4–5% for intracranial infection, 19–33% for seizures, 10% for deep vein thrombosis, and 8% for pulmonary embolus. There were no notable differences in AE rates between the two pivotal Phase III and 26 non-Phase III studies. For the non-pivotal studies, the overall incidence of AEs was low, ranging from 0.2% for intracranial hypertension to 9.6% for healing abnormalities. Healing abnormalities, intracranial infection, and seizures were the most consistently reported AEs, having been observed in 16, 12, and 11 studies, respectively. Rates of healing abnormalities appeared higher in recurrent than in newly diagnosed disease. There were no notable differences between BCNU wafer plus adjuvant treatment (e.g., temozolomide) and BCNU wafer alone, with the exception of haematologic toxicity.

Conclusion: This review of safety data for BCNU wafers provides reassurance that the AE rates reported in current treatment strategies including multimodal treatment approaches are comparable to those observed in the initial registration studies. The broad range of AE rates may reflect differences in the perioperative and postoperative management. Clinical experience suggests that strategies may exist to reduce the risk of complications.     

Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma

Background We investigated the safety, pharmacokinetics, tumor response, and immunological parameters of sorafenib plus interferon α-2a (IFN) in Japanese patients with advanced RCC. Patients and methods After 2 weeks of IFN-alone treatment, eligible patients received 28-day cycles of continuous sorafenib 200 mg (Cohort 1) or 400 mg (Cohorts 2 and 3) twice daily combined with intramuscular IFN 6 (Cohorts 1 and 2) or 9 (Cohort 3) million international units (MIU) three times a week. Results A total of 18 patients received at least one dose of sorafenib plus IFN. Five patients had dose-limiting toxicities (DLTs). The most common DLT was fatigue, experienced in four DLT patients. All 18 patients experienced at least one treatment-emergent adverse event (AE). The most common treatment-emergent AEs included fatigue, fever, platelets, leukocytes, hemoglobin, weight loss and anorexia. Five patients had confirmed partial response and 11 had stable disease, a response rate of 27.8%. IFN had no relevant impact on the pharmacokinetics of sorafenib. Conclusions Sorafenib administered in combination with IFN was well tolerated, with promising results in efficacy. Continuous sorafenib 400 mg twice daily in combination with IFN 6 MIU three times a week is recommended in Japanese patients with advanced RCC.     

Molecular targeted therapy of advanced hepatocellular carcinoma beyond sorafenib

Importance of the field: With the recent advances in the knowledge of molecular biology of hepatocellular carcinoma (HCC), there have been encouraging developments in targeted therapy for advanced HCC.

Areas covered in this review: This review discusses the development of targeted therapy for advanced HCC patient since 2006. Among the newly identified targets, promising results have been shown in targeting the anti-angiogenic pathway. Pure anti-angiogenic agents such as bevacizumab and PTK 787 demonstrate modest activity in treating patients with advanced HCC. Sorafenib, a multi-targeted tyrosine kinase inhibitor with both anti-angiogenic and anti-proliferative effects, has been shown to prolong the overall survival of patients with advanced HCC in two Phase III randomized trials. Like sorafenib, other anti-angiogenic multi-targeted tyrosine kinase inhibitors, such as sunitinib, pazopanib, brivanib and linifanib, also show promising activity in various stages of clinical trials. Other on-going early-phase studies are exploring the activities of drugs targeting novel pathways, such as PI3K/AKT/m TOR, hepatocyte growth factor/mesenchymal epithelial transition factor and insulin-like growth factor.

What the reader will gain: After reading this review, the reader should have an in-depth understanding of the latest developments in the molecular targeted therapy of advanced HCC.

Take home message: The development of sorafenib in the treatment of advanced HCC proves the concept that molecular targeted therapies, especially anti-angiogenic agents, play a pivotal role in the treatment of this otherwise chemoresistant neoplasm. Future progress depends on further unraveling more molecular mechanisms of HCC for therapeutic intervention.