Differences in the Reporting Rates of Serious Allergic Adverse Events From Intravenous Iron by Country and Population

Background: Previous studies have compared rates of adverse events between intravenous (IV) iron preparations; however, there has been no comparison of adverse event rates by country and population. Objectives: To compare rates of adverse events to IV iron products by country and population. Methods: All adverse events reported from 18 countries from January 1, 2003 to June 30, 2009 were obtained for iron dextran (ID), iron sucrose (IS), IS similars (ISS), and sodium ferric gluconate (FG). Rates of all adverse events and serious adverse events (anaphylaxis plus other serious allergic reactions) were calculated as number of events per gram of iron sold (gFe) per million inhabitants (mil) × 10-3. Odds ratios (ORs) were calculated for the risks of adverse events between products. Results: Iron use ranged from 1 gFe/mil (Poland) to 48,674 gFe/mil (Italy). Rates of all adverse events (reports/gFe/mil × 10-3)varied: for IS, it ranged from 0 (Poland, Austria, Czech Republic) to 1,222 (Ireland); for FG, from 3.3 (Czech Republic) to 183.6 (United States); for ID, from 0.9 (Turkey) to 46,875 (Switzerland). There were no reports of adverse events in ISS. In a subset of countries that used 2 or more iron products and had more than 1 serious adverse event, rates (reports/gFe/mil × 10-3)of all adverse events and serious adverse events were lowest for IS (39.8 and 1.7), intermediate for FG (54.8 and 4.5), and greatest for ID (337.7 and 20.5). IS had lower risks for all adverse events (OR, 0.63; P<.0001) and serious adverse events (OR, 0.31; P=.001) versus FG, and for all adverse events (OR, 0.13; P<.0001) and serious adverse events (OR, 0.07; P<.0001) versus ID. FG had lower risks for all adverse events (OR, 0.20; P<.0001) and serious adverse events (OR, 0.24; P<.0001) versus ID. Conclusions: Considerable international variation existed in the extent and choice of iron product and adverse event reporting, suggesting under-reporting in some instances. Clinicians should appreciate the differential risks between available products, and should critically review local reporting practices.

Acquired Hemophilia A: A Current  Review of Autoantibody Disease

Acquired hemophilia A (AHA) is a rare, potentially life-threatening hemorrhagic disorder that presents a complex clinical challenge. The immune-mediated production of autoantibodies, known as factor VIII inhibitors, often results in clinically significant soft tissue or post-procedural bleeding episodes in patients without a previous diagnosis of a bleeding disorder. Acquired antibodies against factor VIII are associated with an extensive list of conditions, including pregnancy, autoimmune disease, and malignancy. There is great potential for morbidity and mortality resulting from autoantibody development. Death is more frequent within the first few weeks after symptomatic manifestation, making prompt recognition and treatment vitally important. Treatment focuses on stabilization of initial bleeding and long-term eradication of the acquired inhibitor. As no randomized clinical trials have been conducted regarding treatment in this patient population, clinical expertise and experience continue to guide treatment recommendations. This report provides an algorithm for the diagnosis of AHA and outlines potential treatment recommendations, most notably concomitant use of recombinant factor VIIa (rF7a) and factor VIII inhibitor bypassing agent to control bleeding in patients not responsive to single-agent therapy, and use of rituximab and prednisone for inhibitor eradication therapy.

Bone Marrow Transplant for Multiple Myeloma: Impact of Distance From the Transplant Center

Purpose: This study investigated the impact of prognostic variables, including the distance a patient lives from a transplant center, on the outcome of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma. Methods: This retrospective analysis included 77 myeloma patients who received an ASCT at Dartmouth Hitchcock Medical Center between 1996 and 2009, 70 of whom were treated between 2002 and 2009. Using linear regression and univariate analysis, we examined the impact of distance from the transplant center on survival. Kaplan-Meier curves identified overall and event-free survival. An association between distance from the transplant center and survival was examined using Cox regression analysis, while adjusting for patient-, disease-, and treatment-related variables. Results: Increasing distance from the transplant center correlated with improved overall survival (P=.004), but had no impact on disease-free survival (P=.26). Conclusions: These results suggest that the distance from a transplant center should not be a barrier to ASCT for eligible patients with multiple myeloma.

Pancreatic Cancer: The Role of Molecular Markers in Diagnosis and Management

Despite an annual incidence of just 40,000 new cases per year, pancreatic adenocarcinoma (PAC) remains the fourth most common cause of cancer-related mortality in the United States, a fact indicative of the considerable diagnostic and therapeutic challenges posed by this malignancy. The availability of increasingly sophisticated molecular techniques over the last decade has intensified the search for biomarkers not only to predict outcome and response to therapy in established pancreatic malignancy but also to identify premalignant pancreatic lesions in at-risk individuals. A wealth of information regarding the complex sequence of genetic abnormalities in PAC has been gained from recent in-depth molecular analyses, and lately the role of epigenetic alterations in the development and maintenance of pancreatic carcinogenesis has been more clearly described. In addition, advances in serum proteomic methods and the collection of circulating tumor cells offer hope for the development of noninvasive techniques for biomarker discovery. At present, we are awaiting the development and validation of robust biomarkers suitable for clinical application in this disease. Herein, we discuss the current status of molecular markers in the diagnosis and management of PAC and review potential clinical applications thereof.

Primary Cytoreductive Surgery for Advanced Ovarian Cancer: Is it the Past, Present, or Future?

Ovarian cancer accounts for more deaths in the United States than all other gynecologic malignancies combined. This is largely due to the fact that no effective screening test has been identified thus far to facilitate early detection. As a result, two-thirds of women continue to be diagnosed with advanced stage III or IV disease. Historically, the standard of care has consisted of primary cytoreductive surgery—with an operative goal of achieving an optimal result with minimal residual disease—followed by adjuvant, platinum-based chemotherapy. However, data suggesting comparable efficacy of neoadjuvant chemotherapy and interval debulking has recently challenged this conventional dogma. The current decision-making on how to initially treat women with newly diagnosed advanced ovarian cancer has become increasingly controversial. This article focuses on whether primary cytoreductive surgery should remain the preferred method of management, or whether it is time for it to be superseded by neoadjuvant chemotherapy.

Pulmonary Toxicities of Tyrosine Kinase Inhibitors

The incidence of pulmonary toxicities with the use of tyrosine kinase inhibitors (TKIs) is not very high; however, various case reports and studies continue to show significant variability in the incidence of these adverse events, ranging from 0.2% to 10.9%. Gefitinib and erlotinib are orally active, small-molecule inhibitors of the epidermal growth factor receptor tyrosine kinase that are mainly used to treat non-small cell lung cancer. Imatinib is an inhibitor of BCR-ABL tyrosine kinase that is used to treat various leukemias, gastrointestinal stromal tumors, and other cancers. In this article, we review data to identify the very rare but fatal pulmonary toxicities (mostly interstitial lung disease) caused by these drugs.

A Phase I Trial of Vatalanib (PTK/ZK) in Combination With Bevacizumab in Patients With Refractory and/or Advanced Malignancies

Background: Vatalanib is an orally active, small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR). Bevacizumab is also an angiogenesis inhibitor, but it possesses a different mechanism of action. This phase I study was conducted to determine the dose-limiting toxicity, maximum-tolerated doses, and recommended phase II doses of the combination of vatalanib and bevacizumab. Patients and Methods: Treatment cycles were 4 weeks in length. Patients received oral vatalanib once or twice daily continuously. Bevacizumab was administered intravenously starting on day 15 of cycle 1, and dosing was repeated at 2-week intervals in patients with at least stable disease for 4 cycles. After 4 cycles, only patients with a partial or complete response continued treatment with the combination of vatalanib and bevacizumab. Patients with stable disease were allowed to continue single-agent vatalanib from cycle 5 until disease progression or intolerable toxicity. Results: A total of 27 patients received 93 cycles of treatment. Dose escalation was difficult due to enhanced toxicities (primarily proteinuria and hypertension) with the regimen that required numerous dose modifications. Interruption of vatalanib and bevacizumab dosing due to proteinuria occurred in 4 patients enrolled at dose level 3, with 1 of these patients developing grade 3 nephrotic range proteinuria. As a result, further dose escalation with the combination regimen was abandoned. Conclusions: Further development of bevacizumab and oral VEGF tyrosine kinase inhibitor combination regimens is questionable due to the additive toxicities that occur; future investigations should proceed with caution.

The Relevance of BRCA Genetics to Prostate Cancer Pathogenesis and Treatment

The breast cancer susceptibility genes 1 (BRCA1) and 2 (BRCA2) are cellular proteins involved in DNA repair. They are normally expressed in the breast, ovaries, prostate, and other tissues. Their germline mutation is the cause of hereditary breast-ovarian cancer syndromes. BRCA mutation carriers are also susceptible to other cancers, notably prostate cancer. In this article, we review the role of BRCA genes in the pathogenesis and clinical course of prostate cancer. We also discuss the molecular mechanisms of action and the therapeutic implications of BRCA germline mutations.

Improving Frontline Treatment for Chronic Myeloid Leukemia: Emerging Evidence for Use of Nilotinib and Dasatinib

The approval of imatinib in 2001 changed the landscape of chronic myeloid leukemia (CML) management, becoming the standard of care and improving the survival rates of patients. With the prevalent use of imatinib worldwide, it was observed that up to one-third of patients are resistant to or intolerant of imatinib therapy, fueling the search for safer and more effective agents. The newer and more potent tyrosine kinase inhibitors nilotinib and dasatinib were first indicated for the treatment of imatinib-resistant/-intolerant patients, for whom these agents are both safe and efficacious. More recent clinical studies have examined nilotinib and dasatinib in the frontline setting in newly diagnosed patients. Data reported from the phase III ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study and the DASISION (Dasatinib versus Imatinib in Patients with Newly Diagnosed Chronic-phase CML) trial support the use of nilotinib and dasatinib as potential new standards for frontline care of newly diagnosed patients with CML in chronic phase. Furthermore, both agents have received regulatory approval for use as frontline agents. These agents have demonstrated significantly superior efficacy compared with imatinib, as measured by complete cytogenetic response and major molecular response rates. In addition, progression to advanced disease was significantly lower for nilotinib, and a trend toward lower progression was observed with dasatinib. Although both nilotinib and dasatinib are generally well tolerated in the frontline setting, they have different safety profiles that may affect their selection as treatment. Understanding the efficacy, safety profiles, and patterns of resistance to various BCR-ABL1 mutations of these newer agents, as well as implementing management strategies to treat adverse events, will help physicians to provide the best therapy options for their patients with CML.

Carcinoma of the Anal Canal: Small Steps in Treatment Advances

For locally advanced squamous cell carcinoma of the anal canal, efforts to discover effective treatments that would protect sphincter preservation led to the development of combined chemoradiotherapy, which, when administered appropriately, is curative. While the standard of combined modality chemoradiotherapy has minimally changed over the past 30 years, various chemotherapeutic and biologic agents, as well as novel methods for delivering radiation, have enhanced the treatment of anal carcinoma and are continuously being explored. This review examines the risk factors associated with anal carcinoma, and subsequently discusses the current standard of care from diagnosis through surveillance, paying attention to the pivotal trials that have shaped modern treatment paradigms.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a growing complication of a common medication used to prevent deep vein thrombosis (DVT) in hospitalized patients. The purpose of this article is to review the mechanism that causes paradoxical thrombus formation in HIT and ways to recognize this important complication with various testing modalities and to discuss the approaches to treatment once a diagnosis has been made. HIT is a clinical diagnosis that can be further supported by utilizing the “4 Ts”: thrombocytopenia, timing of platelet count fall, thrombosis or other complications, and other causes for thrombocytopenia. Diagnosis of HIT can be established using an HIT antibody test. Once a drop in platelet count is observed in a patient, it is important to rule out HIT. When HIT is first suspected, it is important to discontinue all heparin products. The gold standard in diagnosing HIT is the 14C-serotonin release assay (14C-SRA) assay, which has high sensitivity and specificity but is technically demanding and more time consuming than other antibody-detecting immunoassays. Anticoagulation in HIT patients is essential due to the increased risk of thrombosis. Treatment consists of utilizing alternative, nonheparin anticoagulants like lepirudin, argatroban, bivalirudin, or fondaparinux (although fondaparinux is not formally approved by the US Food and Drug Administration for this condition). Each of these agents should be individually formulated based on the patient and the presence/absence of liver or renal failure. Treatment duration has yet to be determined. However, in patients requiring long-term anticoagulation (pulmonary embolism, DVT, stroke), the transition to warfarin can be made once the platelet count recovers and there has been at least 5 days of overlap with a nonheparin anticoagulant.

Update on Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, which is classically associated with signs and symptoms of fever, thrombocytopenia, neurologic deficits, hemolytic anemia, and renal failure. It is caused by a deficiency of A Disintegrin-like And Metalloprotease with a ThromboSpondin type1 motif 13 (ADAMTS13), which may be an inherited disorder, but more commonly is an acquired disease due to autoantibodies directed against ADAMTS13. Low ADAMTS13 levels result in increased ultra-large von Willebrand factor multimers, which induce platelet adhesion and thrombosis. Plasma exchange therapy is the standard of care, and has greatly reduced morbidity and mortality. A recent TTP case is reviewed, and treatments for recurrent or refractory TTP are summarized. A scoring system using clinical and laboratory parameters to evaluate which suspected TTP patients will benefit from plasma exchange therapy is also discussed.

Telomerase Targeted Therapy in Cancer and Cancer Stem Cells

Telomerase plays a key role in cell fate: loss of telomerase in normal differentiated cells heralds senescence and limits cell division, whereas reactivation of telomerase sustains proliferation and potentiates mutagenesis and transformation. Given this pivotal role, telomerase has been the subject of intense investigation in the field of developmental cancer therapeutics. To date, a broad spectrum of therapeutic strategies has been developed, ranging from direct targeting or reprogramming of the enzyme, to immune or virus-mediated targeting of cells expressing telomerase, to strategies focusing on the telomeres themselves. The recent discovery and growing interest in cancer stem cells has thrust telomerase therapy into new relief as an approach that may be uniquely suited to neutralizing this treatment-resistant subpopulation of cancer cells. Here we will review the mechanistic rationale and preclinical and clinical state of development of the various telomerase-based therapeutic approaches, with emphasis on the role of telomerase in cancer stem cell biology and its implications for therapeutic efforts.

Alemtuzumab: What Is the Secret to Safe Therapy?

Over the past decade, the use of the monoclonal antibody alemtuzumab in chronic lymphocytic leukemia has expanded from administration as a single-agent therapy, into use in combination with fludarabine or rituximab, and further to use as a consolidation agent with the goal of eradicating minimal residual disease. Numerous clinical studies have shown that alemtuzumab is effective as first-line treatment and in patients who have relapsed disease or who are refractory to fludarabine. Despite improvements in response rates and survival compared with combination chemotherapy, there remains some hesitation to incorporate alemtuzumab into management because of known toxicities. Adverse events in patients treated with standard-dose, single-agent alemtuzumab occur at generally predictable time points during treatment and can be managed effectively; this outcome is less established when alemtuzumab is incorporated into combination regimens. Variability in alemtuzumab dosing, route of administration, and duration of therapy has led to inconsistent and sometimes adverse safety consequences. This article presents an overview of clinical studies with alemtuzumab as a single agent, in combination, or in consolidation, with discussion of toxicity and suggestions for ensuring that the efficacious outcomes following alemtuzumab therapy are not outweighed by safety concerns.

Non-Small Cell Lung Cancer Therapy in the Elderly

To date, lung cancer is still the leading cause of cancer-related mortality worldwide, with the majority of lung cancers arising in the elderly. As a consequence, we can expect an increase in the number of older lung cancer patients considered suitable for chemotherapy in the near future. Elderly patients often have comorbid conditions and progressive physiologic reduction of organ function, which can make the selection of proper treatment daunting. Some patients will be able to tolerate chemotherapy as well as their younger counterparts, whereas others will experience severe toxicity and require treatment modifications. Thus, a major issue is effectively selecting patients suitable for standard or attenuated therapy. A comprehensive geriatric assessment performed at baseline is a useful tool that can help select the best treatment regimen to be administered to elderly patients. Until now, few trials have specifically focused on elderly patients affected by non-small cell lung cancer (NSCLC), particularly those with advanced disease; prospective elderly-specific studies in early stages are still lacking. High priority should be given to evaluating the role of new targeted therapies. Unfortunately, to date, clinical trials that include functional status and comorbidity as part of the geriatric assessment are rare. Future trials, specifically in the elderly population, should include these kinds of evaluations. The most recent therapies for the treatment of elderly patients with NSCLC will be discussed here.

A Pilot Study of Adjuvant Doxorubicin and Cyclophosphamide Followed by Paclitaxel and Sorafenib in Women With Node-Positive or High-Risk Early-Stage Breast Cancer

To examine the safety of sorafenib combined with standard adjuvant treatment in patients with node-positive or otherwise high-risk breast cancer. Patients and Methods: Eligibility: mastectomy/breast-conserving surgery; axillary node assessment for stage I/II/IIIA/IIIC (T1–3, N3a only) breast cancer; node-positive/high-risk node-negative (tumor size >2 cm; hormone-receptor negative; grade 2/3; or age <35 years); Eastern Cooperative Oncology Group performance status (ECOG-PS) 0–1; and adequate organ function. Treatment: doxorubicin (60 mg/m2 intravenous) and cyclophosphamide (600 mg/m2 intravenous; AC) on day 1, every 3 weeks (x 4 cycles), followed by paclitaxel 175 mg/m2 intravenous on day 1, (every 3 weeks x 4 cycles) or 80 mg/m2 intravenous (every week/x 12 cycles), combined with sorafenib (400 mg oral twice a week; TS) for 12 months or less. Results: Forty-five patients were enrolled from 5/07–1/08. Baseline characteristics included: median age of 54 years (range, 35–74 years); 93% of patients with ECOG-PS 0; 84% node-positive; 33% hormone-receptor negative. All patients completed AC treatment and were eligible to receive TS; of these, 8 (13%) patients came off study due to physician/patient decision; 21 (47%) patients came off study due to toxicity; 2 (4%) patients completed TS but did not proceed with maintenance sorafenib; and 14 (31%) patients completed TS and entered the maintenance phase of sorafenib treatment. Sorafenib was taken for 6.1 weeks during the paclitaxel phase and 15 weeks during maintenance. Severe toxicities during sorafenib therapy were limited, including neutropenia, anorexia, arthralgia, diarrhea, and dyspnea. After a median follow-up of 21.0 months (range, 18.9–25.9), all patients were alive and without recurrence. Conclusion: Sorafenib was generally associated with limited severe toxicity when combined with paclitaxel following AC. However, many patients discontinued sorafenib early due to grade 1/2 toxicity, physician/patient decision, and treatment compliance. Additional studies of sorafenib in breast cancer in the neoadjuvant and triple-negative settings are warranted.

Bisphosphonates in Breast Cancer: Clinical Activity and Implications of Preclinical Data

Rebecca Aft, MD, PhD Dr. Aft is a Professor of Surgery in the Division of General Surgery at the Washington University School of Medicine in St. […]

A Phase I Study of Panobinostat in Combination With Gemcitabine in the Treatment of Solid Tumors

Purpose: To evaluate the safety and tolerability of the combination of orally administered panobinostat with gemcitabine in patients with advanced solid tumors. Patients and methods: Patients received oral panobinostat administered 2 or 3 times weekly (continuous or intermittent dosing in combination with intravenous gemcitabine administered on days 1, 8, and 15 every 28 days or on days 1 and 8 every 21 days). Toxicity assessments were ongoing, and disease assessments were repeated every 2 treatment cycles. Results: A total of 63 cycles of study treatment were administered to 17 patients over 5 different dose levels. Dose-limiting toxicities occurred at all dose levels. In all instances, dose-limiting toxicities were due to grade 4 myelosuppression or myelosuppression warranting dose modifications during the first treatment cycle. Nonhematologic toxicities were mild to moderate in intensity and consisted of anorexia, constipation, diarrhea, fatigue, nausea, vomiting, and rash. One patient with ovarian cancer had an unconfirmed partial response, and 5 patients had stable disease lasting more than 4 cycles. Conclusion: Dosing of the combination regimen of panobinostat and gemcitabine is limited by myelosuppression. The recommended doses for further study are intermittent oral panobinostat administered at a dose of 10 mg 3 times weekly for 2 weeks in combination with gemcitabine 800 mg/m2 administered intravenously on days 1 and 8 every 21 days.

Resistance to Angiogenesis Inhibitors in Renal Cell Carcinoma

Antiangiogenic drugs are now available for treatment of renal cell carcinoma and are utilized sequentially to prolong clinical benefit in patients with recurrent disease. These antiangiogenic agents are disease stabilizing in most cases, and resistance eventually develops over time. Because different combinations and sequences are tested in clinical trials, resistance patterns and mechanisms should be investigated. Much effort has been devoted to understanding the biology and elucidating the pathways and additional targets during tumorigenesis and metastasis. Resistance appears to be either primary nonresponsiveness, or it is acquired over time and related to various evasive/escape mechanisms that the tumor develops in response to therapy. Primary resistance is less common, but may be due to an intrinsic redundancy of available angiogenic signals for the tumor, causing unresponsiveness to vascular endothelial growth factor (VEGF)-targeted therapies. During acquired resistance, tumors may activate an “angiogenic switch,” which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Rationally designed preclinical and clinical trials will shed additional light on our understanding of the potential mechanisms of resistance to antiangiogenic drugs.

Local Therapy for the Primary Breast Tumor in Women With Metastatic Disease

The management of de novo stage IV breast cancer focuses on systemic therapy for distant sites. The underlying assumption is that such therapy will control the primary tumor sufficiently well for the remainder of the patient’s life, and that specific therapy for the primary tumor is not beneficial. This concept is being re-evaluated because of the lengthening survival of stage IV patients, the tendency towards decreasing metastatic disease burden at diagnosis, and accumulating data suggesting that local therapy for the primary site may be beneficial. Retrospective data on more than 30,000 women from North America and Europe have now been published, showing a robust association between surgery or radiotherapy for the primary tumor and prolonged survival. Many questions remain, most importantly, whether this observed association reflects a selection of women with good prognosis for primary site therapy; others relate to the fraction of women in published studies who were diagnosed with metastatic disease postoperatively, whether specific subsets would derive greater benefit, and the appropriate timing and extent of local therapy. These issues can be definitively addressed only in a randomized trial. Two trials are open in India and Turkey; a third is being planned in the United States and is expected to open in 2011. Given the importance of these questions for the approximately 10,000 women who are diagnosed with stage IV breast cancer in the United States—and the many more worldwide—it is hoped that the US trial will receive strong support from breast cancer physicians and from our patients.