Afatinib for the treatment of EGFR mutation-positive NSCLC: A review of clinical findings.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors represent the standard of care in patients with EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). The availability of several EGFR tyrosine kinase inhibitors approved for use in the first-line or later settings in NSCLC warrants an in-depth understanding of the pharmacological properties of, and clinical data supporting, these agents. The second-generation, irreversible ErbB-family blocker, afatinib, has been extensively studied in the context of EGFRm+ NSCLC. Results from the LUX-Lung 3 and 6 studies showed that afatinib was more active and better tolerated than chemotherapy in patients with tumors harboring EGFR mutations. Subanalysis of these trials, along with real-world data, indicates that afatinib is active in patients with certain uncommon EGFR mutations (S768I/G719X/L861Q) as well as common mutations (Del19/L858R), and in patients with active brain metastases. In LUX-Lung 7, a head-to-head phase IIb trial, afatinib improved progression-free survival and time-to-treatment failure versus the first-generation reversible EGFR tyrosine kinase inhibitor, gefitinib, albeit with a higher incidence of serious treatment-related adverse events. Nevertheless, afatinib is generally well tolerated, and adverse events are manageable through supportive care and a well-defined tolerability-guided dose adjustment scheme. In this review, we provide a detailed overview of the pharmacology, efficacy, and safety of afatinib, discuss treatment sequencing strategies following emergence of different resistance mechanisms, and shed light on the economic impact of afatinib. We also provide a comparison of afatinib with the available EGFR tyrosine kinase inhibitors and discuss its position within treatment strategies for patients with EGFRm+ NSCLC.

Association of hypertension and treatment outcomes in advanced stage non-small cell lung cancer patients treated with bevacizumab or non-bevacizumab containing regimens.

Background Studies suggest that bevacizumab-induced hypertension is prognostic of better outcomes in bevacizumab-treated patients with metastatic colorectal, HER2-negative breast, kidney, and pancreatic cancer. Few have examined this correlation in metastatic non-small cell lung cancer and evaluated whether hypertension independent of bevacizumab can improve the treatment outcomes. Objectives The primary objective was to determine the effect of hypertension on the overall response of advanced non-small cell lung cancer patients from start of the first-line chemotherapy to maintenance therapy. Secondary objectives include the effect of hypertension on the overall survival in all patients and on the overall response in bevacizumab-treated patients. Methods A retrospective chart review for a single institution was conducted from 2008 to 2013 on all patients with advanced non-squamous non-small cell lung cancer who received ≥ 1 cycle of combination chemotherapy. Patients were divided into hypertension versus no hypertension and into bevacizumab versus non-bevacizumab groups. Results Of the 188 advanced non-small cell lung cancer patients evaluated, 62 were treated with bevacizumab-containing regimens. The mean age at diagnosis was 58 years in both the groups. Hypertension independent of bevacizumab did not lead to improved treatment outcomes. However, in the bevacizumab subgroup, hypertensive patients had significantly higher response rates versus non-hypertensive patients (36.7% vs. 12.5%; p = 0.02). There was no significant difference in the overall survival between hypertensive versus non-hypertensive patients. Conclusion While hypertension alone did not significantly improve the treatment outcomes, hypertension in bevacizumab-treated patients with metastatic non-small cell lung cancer led to significantly improved responses. Further prospective studies are needed to confirm the association of hypertension with improved treatment outcomes in metastatic NSCLC.

Association of time to antibiotics and clinical outcomes in adult hematologic malignancy patients with febrile neutropenia.

Objective The objective of this study was to determine the clinical impact of time to antibiotic administration in adult inpatients who have hematologic malignancies and develop febrile neutropenia. Methods A retrospective chart review was conducted to screen for all febrile neutropenia events amongst adult hematologic malignancy patients between 1 January 2010 and 1 September 2014. All included patients were admitted to the hospital at the time of fever onset, having been admitted for a diagnosis other than febrile neutropenia. Descriptive statistics and logistic generalized estimated equations were used to analyze the data. Results Two hundred forty-four neutropenic fever events met inclusion criteria. Thirty-five events (14.34%) led to negative clinical outcomes (in-hospital mortality, intensive care unit transfer, or vasopressor requirement), with an in-house mortality rate of 7.4%. The time to antibiotics ranged from 10 min to 1495 min. The median time to antibiotics in the events that led to negative outcomes was 120 min compared to 102 min in the events that did not lead to the negative outcome ( p = 0.93). Conditional order sets were used to order empiric antibiotics in 176 events (72.1%) and significantly reduced time to antibiotics from 287 min to 143 min ( p = 0.0019). Conclusion Prolonged time to antibiotic administration in hematologic malignancy patients who develop neutropenic fever was not shown to be associated with negative clinical outcomes.

Capecitabine-induced ventricular fibrillation arrest: Possible Kounis syndrome.

We report the case of capecitabine-induced ventricular fibrillation arrest, possibly secondary to type I Kounis syndrome. A 47-year-old man with a history of T3N1 moderately differentiated adenocarcinoma of the colon, status-post sigmoid resection, was started on adjuvant capecitabine approximately five months prior to presentation of cardiac arrest secondary to ventricular fibrillation. An electrocardiogram (EKG) revealed ST segment elevation on the lateral leads and the patient was taken emergently to the cardiac catheterization laboratory. The catheterization revealed no angiographically significant stenosis and coronary artery disease was ruled out. After ruling out other causes of cardiac arrest, the working diagnosis was capecitabine-induced ventricular fibrillation arrest. As such, an inflammatory work up was sent to evaluate for the possibility of a capecitabine hypersensitivity, or Kounis syndrome, and is the first documented report in the literature to do so when evaluating Kounis syndrome. Immunoglobulin E (IgE), tryptase, and C-reactive protein were normal but histamine, interleukin (IL)-6, and IL-10 were elevated. Histamine elevation supports the suspicion that our patient had type I Kounis syndrome. Naranjo adverse drug reaction probability scale indicates a probable adverse effect due to capecitabine with seven points. A case of capecitabine-induced ventricular fibrillation arrest is reported, with a potential for type 1 Kounis syndrome as an underlying pathology supported by immunologic work up.

Pharmacokinetics of intravenous levofloxacin administered at 750 milligrams in obese adults.

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

Sticky Issues: What APs Need to Know About Anticoagulants and Patients With Cancer.

During the JADPRO Live Virtual 2020 conference, Val R. Adams, PharmD, FCCP, FHOPA, BCOP, discussed how to determine which patients with cancer should be treated with direct oral anticoagulants (DOACs), the similarities and differences between the DOACs, and recent data on the prevention and treatment of cancer-associated venous thromboembolism.

Inactivation of the ketoreductase gilU gene of the gilvocarcin biosynthetic gene cluster yields new analogues with partly improved biological activity.

Four new analogues of the gilvocarcin-type aryl-C-glycoside antitumor compounds, namely 4'-hydroxy gilvocarcin V (4'-OH-GV), 4'-hydroxy gilvocarcin M, 4'-hydroxy gilvocarcin E and 12-demethyl-defucogilvocarcin V, were produced through inactivation of the gilU gene. The 4'-OH-analogues showed improved activity against lung cancer cell lines as compared to their parent compounds without 4'-OH group (gilvocarcins V and E). The structures of the sugar-containing new mutant products indicate that the enzyme GilU acts as an unusual ketoreductase involved in the biosynthesis of the C-glycosidically linked deoxysugar moiety of the gilvocarcins. The structures of the new gilvocarcins indicate substrate flexibility of the post-polyketide synthase modifying enzymes, particularly the C-glycosyltransferase and the enzyme responsible for the sugar ring contraction. The results also shed light into biosynthetic sequence of events in the late steps of biosynthetic pathway of gilvocarcin V.

Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment.

BACKGROUND: The Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS-BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS-BLED score in a large cohort of VTE patients. METHODS AND RESULTS: A retrospective cohort of adults ≥18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS-BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS-BLED scores of 0 to 2, 3.6% score ≥4, and 4789 bleeding events (3.6% all patients). A 1-point HAS-BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3- to 4-points was significant for all bleeds (csHR=1.41, 95% CI: 1.17-1.69; sdHR=1.40, 95% CI: 1.17-1.69) and major bleeds (csHR=1.66, 95% CI: 1.26-2.20; sdHR=1.66, 95% CI: 1.25-2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98-2.56) and sdHR=2.11 (95% CI: 1.85-2.41) in the model for major bleeds. CONCLUSIONS: The HAS-BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the "B" criterion ("bleeding tendency or predisposition").

Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors.

BACKGROUND: Sunitinib was approved by the US Food and Drug Administration (FDA) on January 26, 2006, for the treatment of metastatic renal cell carcinoma (mRCC) and gastrointestinal stromal tumor (GIST) in patients who have failed to respond to imatinib or were unable to tolerate it. OBJECTIVE: This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of sunitinib; potential drug interactions; and the results of clinical trials evaluating its efficacy and tolerability. METHODS: Pertinent literature was identified by searches of MEDLINE (1966-January 31, 2007), the American Society of Clinical Oncology abstracts database (2000-2007 annual meetings/symposia and previous meetings), and the FDA Web site (October 2006). Search terms included, but were not limited to, sunitinib, SUl1248, renal cell carcinoma, gastrointestinal stromal tumor, pharmacology, pharmacokinetic, adverse events, and clinical trial. Additional publications were found by scanning the reference lists of the identified articles. RESULTS: Sunitinib is a potent inhibitor of multiple tyrosine kinase receptors. Its Tmax is reached within 6 to 12 hours, and food does not appear to affect its bioavailability. Sunitinib is metabolized by cytochrome P450 (CYP) 3A4 to an active metabolite, SU12662, which is further metabolized by CYP3A4 to an inactive moiety. The parent compound and active metabolite have similar biochemical activity and potency and reach similar plasma concentrations. Sunitinib and SU12662 have a tl/2 of 40 to 60 hours and 80 to 110 hours, respectively. Steady-state concentrations of both active entities are reached after 10 to 14 days of therapy. In a Phase III trial comparing sunitinib with interferon-alfa (IFN-00 as first-line therapy for mRCC, sunitinib was associated with a median progression-free survival of 11 months, compared with 5 months with IFN-cz (P < 0.001). A randomized, double-blind, placebo-controlled trial evaluating sunitinib as second-line therapy for GIST found a median time to progression of 28.9 weeks in the sunitinib arm, compared with 7 weeks in the placebo arm (hazard ratio = 0.28; P < 0.001). In Phase II trials, sunitinib also had anti-tumor activity in patients with breast cancer, neuroendocrine tumors, and non-small cell lung cancer. Further evaluation in these tumors, as well as in patients with acute myelogenous leukemia, may lead to expanded indications. The approved dose of sunitinib is 50 mg/d PO for 4 weeks, followed by a 2-week rest; this pattern is repeated until tumor progression or the occurrence of intolerable adverse effects. The most common clinical toxicities attributable to sunitinib include diarrhea, mucositis/stomatitis, hypertension, rash, skin discoloration, and altered taste, whereas commonly occurring laboratory abnormalities have been seen in association with gastrointestinal toxicity, renal toxicity, and hematologic toxicity. Of grade 3/4 toxicities occurring with sunitinib (which are relatively uncommon [<10%]), those that are clinically important include hypertension, diarrhea, fatigue, and hand-foot syndrome. CONCLUSIONS: Sunitinib is a multiple tyrosine kinase receptor inhibitor approved for the treatment of mRCC and GIST. Evidence for long-term clinical benefit in renal cell cancer and other tumors awaits the results of ongoing trials.

Targeting the PD-1 pathway in pediatric solid tumors and brain tumors.

While remarkable advances have been made in the treatment of pediatric leukemia over the past decades, new therapies are needed for children with advanced solid tumors and high-grade brain tumors who fail standard chemotherapy regimens. Immunotherapy with immune checkpoint inhibitors acting through the programmed cell death-1 (PD-1) pathway has shown efficacy in some chemotherapy-resistant adult cancers, generating interest that these agents may also be helpful to treat certain refractory pediatric malignancies. In this manuscript we review current strategies for targeting the PD-1 pathway, highlighting putative biomarkers and the rationale for investigation of these drugs to treat common pediatric tumors such as sarcoma, neuroblastoma, and high-grade glioma. We summarize the completed and ongoing clinical trial data available, and suggest potential applications for further study.

Statin use and venous thromboembolism in cancer: A large, active comparator, propensity score matched cohort study.

BACKGROUND: Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010-2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE outcomes reporting the hazard ratios (HR) between the treatment groups. Sensitivity analyses assessed the influence of age and individual medications. RESULTS: The total cohort included 170,459 patients, which, after matching, were similar on baseline characteristics. The overall model showed a statistically significant protective effect for statins compared to no treatment attributed only to leukemia for DVT (HR=0.77, 95% CI 0.61-0.99) and colorectal cancers for PE (HR=0.80, 95% CI 0.64-0.99) in stratified analyses. There were generally no differences in outcomes between statins and non-statins and no individual statin use showed results different from the class effect. CONCLUSIONS: In this propensity score matched sample of patients with cancer, statins were shown to have a small protective effect in some cancers for DVT or PE compared to no treatment and little difference compared to an active control group. The lack of effect was consistent across statins and was also not found for any of the sensitivity analyses included.

Vena Cava Filter Retrieval Rates and Factors Associated With Retrieval in a Large US Cohort.

BACKGROUND: Retrieval of vena cava filters (VCFs) is important for safety as complications increase with longer dwell times. This study assessed VCF retrieval rates and factors associated with retrieval in a national cohort. METHODS AND RESULTS: VCFs were identified by procedural codes from an administrative claims database. Patients were identified who had a VCF placement during a hospitalization from a national commercial administrative claims database. Indications for VCF placement were identified as pulmonary embolism with or without deep vein thrombosis, deep vein thrombosis only, or prophylactic. Patient demographic and clinical characteristics were included in proportional hazard regression models to find associations with early (90-day) and 1-year VCF retrieval. Initiation of anticoagulation and the correlation between time-to-retrieval and time-to-initiation of anticoagulation were observed. Of 54 766 patients receiving a VCF, 36.9% had pulmonary embolism, 43.9% had deep vein thrombosis only, and 19.2% had no apparent venous thromboembolism present. Over the 1 year of follow-up, the cumulative incidence of VCF retrieval was 18.4%. Retrieval increased over time from a low of 14.0% in 2010 up to ≈24% in 2014. In adjusted time-to-event models, increasing age, differing regions, and some comorbidities were associated with poorer retrieval rates. Initiation of anticoagulation was poorly correlated with retrieval, with anticoagulation preceding retrieval by a median of 51 days while those without retrieval had a median of 278 days of exposure to anticoagulation. CONCLUSIONS: VCF retrieval increased over the study period but remained suboptimal and was weakly correlated with anticoagulation initiation.

Evolving role of antineoplastic agents in colorectal cancer.

PURPOSE: The epidemiology, natural history, patient presentation, staging, prognosis, and treatment of colorectal cancer are described. SUMMARY: Colorectal cancer is a common malignancy that usually is not diagnosed when it is localized because it typically is asymptomatic in the early stages. Various cancer chemotherapeutic agents with different toxicities are available, including the recently introduced recombinant humanized immunoglobulin G(1) monoclonal antibodies cetuximab and bevacizumab. Chemotherapy may be used with or without surgery in patients with advanced or metastatic colorectal cancer, usually for palliation rather than a cure. The results of clinical trials suggest that patients with advanced or metastatic colorectal cancer probably should receive 5-fluorouracil (5-FU)/leucovorin, irinotecan, oxaliplatin, bevacizumab, and cetuximab at some time in the course of treatment, although the preferred combinations and sequence of these agents remain to be determined. After surgery, adjuvant chemotherapy may be used for curative purposes in patients with stage III disease and some patients with stage II disease at high risk for disease recurrence and death. Although 5-FU plus leucovorin has been the standard adjuvant therapy, clinical trials have demonstrated that adding oxaliplatin or using capecitabine alone instead is an alternative. CONCLUSION: Several recently introduced chemotherapeutic agents appear promising for the treatment of colorectal cancer, but additional clinical research is needed to identify the ideal combinations and sequence of these agents.

PD-1 Pathway Inhibitors: Immuno-Oncology Agents for Restoring Antitumor Immune Responses.

Immune checkpoint inhibitors are designed to restore a patient's own antitumor immune response that has been suppressed during tumor development. The first monoclonal antibodies against the immune checkpoint programmed death 1 (PD-1) receptor, nivolumab and pembrolizumab, are now approved for clinical use. Both agents are indicated for the treatment of advanced melanoma, as well as for the treatment of metastatic non-small cell lung cancer (NSCLC). Nivolumab is also approved for the treatment of advanced renal cell carcinoma. In patients with melanoma, these agents result in objective response rates of ~25-40%, with durable responses lasting more than 2 years in some cases. Results from phase III trials have shown improved survival with nivolumab versus standard-of-care chemotherapy in both patients with advanced melanoma and those with advanced NSCLC. In patients with advanced melanoma, both PD-1 inhibitors (nivolumab and pembrolizumab) have shown improved survival versus ipilimumab. PD-1 inhibitors are associated with adverse events that have immune etiologies, with grade greater than 3 adverse events typically reported in 16% or less of patients. However, most immune-mediated adverse events (including grade 3-4 adverse events) can be managed by using published management algorithms without permanent discontinuation of the agent. As nivolumab and pembrolizumab enter the clinic, and with more PD-1 pathway agents in development for a range of tumor types, this review aims to provide pharmacists with a basic understanding of the role of PD-1 in modulating the immune system and their use in the cancer treatment. The most recent clinical efficacy and safety data are discussed, highlighting the response characteristics distinctive to immune checkpoint inhibitors, along with pharmacokinetic and pharmacodynamic data and cost considerations.

Incidence and Risk Factors of Thromboembolism with Multiple Myeloma in the Presence of Death as a Competing Risk: An Empirical Comparison of Statistical Methodologies.

Multiple myeloma (MM) has an inherent high risk of thromboembolic events associated with patient as well as disease- and treatment-related factors. Previous studies have assessed the association of MM-related thromboembolism using "traditional" Kaplan-Meier (KM) and/or Cox proportional hazard (PH) regression. In the presence of high incidence of death, as would be the case in cancer patients with advanced age, these statistical models will produce bias estimates. Instead, a competing risk framework should be used. This study assessed the baseline patient demographic and clinical characteristics associated with MM-related thromboembolism and compared the cumulative incidence and the measures of association obtained using each statistical approach. The cumulative incidence of thromboembolism was 9.2% using the competing risk framework and nearly 12% using the KM approach. Bias in the measures of covariate risk associations was highest for factors related to risk of death such as increased age (75% bias) and severe liver disease (50%) for the Cox PH model compared to the competing risk model. These results show that correct specification of statistical techniques can have a large impact on the results obtained.

Impact of Time-Varying Treatment Exposures on the Risk of Venous Thromboembolism in Multiple Myeloma.

Multiple myeloma (MM) has one of the highest risks of venous thromboembolism (VTE) of all cancers due to pathologic changes and treatment-related exposures. This study assessed the one-year incidence of VTE in newly diagnosed MM and to determine the baseline and time-varying treatment-related factors associated with VTE risk in a U.S.-based cohort. MM patients were identified and age, gender, and baseline comorbidities were determined. Treatment-related exposures included thalidomide derivatives (IMIDs), proteasome inhibitors, cytotoxic chemotherapy, steroids, erythropoietin-stimulating agents (ESAs), stem cell transplants (SCT), hospitalizations, infection, and central venous catheters (CVC). Multiple statistical models were used including a baseline competing risks model, a time-varying exposure Cox proportional hazard (CPH) model, and a case-time-control analysis. The overall incidence of VTE was 107.2 per 1000 person-years with one-half of the VTEs occurring in the first 90 days. The baseline model showed that increasing age, heart failure, and hypertension were associated with one-year incidence of VTE. MM-specific IMID treatment had lower than expected associations with VTE based on prior literature. Instead, exposure to ESAs, SCT, CVC, and infection had higher associations. Based on these results, VTE risk in MM may be less straightforward than considering only chemotherapy exposures, and other treatment-related exposures should be considered to determine patient risk.

Competing Risks Analysis of Cancer-associated Recurrent Thrombosis, Major Bleeds, and Death in a Geriatric Cohort.

Background: Individuals with cancer are at an increased risk of venous thromboembolism (VTE). There is a continued increased risk of recurrent VTE after the initial event as well as increased bleed risk related to VTE treatment. Objectives: This study sought to observe the incidence of recurrent VTE, major bleeding, and death in a geriatric oncology population during treatment for a cancer-associated VTE. Methods: We utilized an insurance claims database of Medicare Advantage beneficiaries 65 and older. The index VTE was identified and individuals were followed up to 180 days to observe an outcome event. Treatment groups were classified among those receiving warfarin, low-molecular weight heparins (LMWH), vena cava (VC) filters with or without anticoagulation, or no treatment. Treatment groups were compared on baseline demographic and clinical characteristics and an inverse probability of treatment weight was used to balance these factors between the groups. A competing risks, time-to-event analysis was performed including treatment only models as well as adjusted models with additional covariates. Causespecific hazards ratios (HRs) and their 95% confidence intervals were reported. Results: Treatment groups differed on baseline variables including age, comorbidities, and tumor sites. After balancing the treatment groups on baseline characteristics, those receiving LMWHs had no difference in recurrent VTE compared to warfarin but had less than half the risk of major bleeding (HR=0.48 [0.27-0.85]). Those receiving VC filters had increased risk of all outcome events relative to warfarin. Conclusions: Patients over the age of 65 with cancer are at a high risk of experiencing recurrent VTE and major bleeding during treatment for a cancer-associated VTE. These results are consistent with United States guidelines which recommend LMWHs over warfarin for treatment and secondary prevention of VTE.

The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells.

PURPOSE: To determine the in vitro drug sensitivity of two non-small-cell lung cancer cell lines after treatment with the novel lipophilic camptothecin derivative, 7- tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), to determine if topoisomerase I protein levels decrease after treatment with DB-67, and to assess the duration and extent of topoisomerase I modulation after DB-67 exposure, in order to provide information about drug resistance that may be useful in determining an appropriate dosing schedule for DB-67. METHODS: The growth inhibition of the non-small-cell lung cancer cell lines A549 and H460 after exposure to DB-67 was evaluated with the MTS assay. A549 and H460 cells were treated for various times with DB-67 and topoisomerase I levels were determined by western blot analysis. In addition, A549 and H460 cells were treated with DB-67 for 24 h and topoisomerase I levels were determined by western blot analysis daily for 1 week after drug removal. RESULTS: DB-67 inhibited the growth of both A549 and H460 cells grown in culture; the A549 cells were more resistant to the cytotoxic effects of DB-67 than H460 cells. Notably, A549 cells had approximately one-half the baseline topoisomerase I than H460 cells. Topoisomerase I protein levels significantly decreased after 8-18 h of exposure to DB-67. Both A549 and H460 cells treated with DB-67 for 24 h had only negligible amounts of topoisomerase I at the end of treatment. However, within 24 h of drug removal topoisomerase I levels returned to near baseline levels in both cell lines. CONCLUSIONS: The decrease in topoisomerase I levels caused by DB-67 may represent a mechanism of resistance to this novel camptothecin derivative. Dosing DB-67 once every 48-72 h may maximize the interaction of the drug with topoisomerase I and should be considered as a potential dosing schedule in the preclinical and clinical development of this compound.

The reversal of inhibitors in congenital hemophilia.

Hemophilias A and B are heritable bleeding disorders characterized by deficient baseline levels of factor VIII (fVIII) and factor IX (fIX), respectively. Standard treatment for acute bleeding events and for prophylaxis in patients with severe disease consists of recombinant fVIII and fIX infusions. The development of alloantibodies, or inhibitors, is a serious complication of congenital hemophilia that may impair the effectiveness of fVIII and fIX, leading to increased morbidity and cost of therapy. When inhibitors are present, bypassing agents such as recombinant activated factor VII and factor eight inhibitor bypass agent are available for treatment of bleeding events. Although usually effective, they are costly treatments. Immune-modulatory therapy may reverse inhibitors, allowing fVIII and fIX to be used again. Immune tolerance induction is the chief treatment option to decrease inhibitor levels, but about 20-30% of patients fail this treatment. Alternatively, multiple immune-modulating agents have been tried with limited success. Rituximab, an anti-CD20 monoclonal antibody, is one therapy that has been successful in reducing inhibitor titers in multiple case reports. Although current evidence is limited and questions regarding its use and place in therapy still exist, this agent shows promise for the future.

Histological and genetic markers for non-small-cell lung cancer: customizing treatment based on individual tumor biology.

PURPOSE: To describe how molecular and genetic markers influence the response to therapy in patients with advanced non-small-cell lung cancer (NSCLC). SUMMARY: Cisplatin resistance has been associated with high rates of expression of endonucleases, a family of DNA repair proteins that includes ERCC1 and BRCA1. Gemcitabine is thought to produce its antitumor effects by several mechanisms, including inhibition of ribonucleotide conversion to deoxyribonucleotide through the inactivation of ribonucleotide reductase. One type of gemcitabine resistance occurs when the inactivation of ribonucleotide reductase decreases, which correlates with increased expression of the M1 subunit of ribonucleotide reductase. Taxanes produce their anti-tumor effects by binding to and stabilizing intracellular microtubules, which are necessary for DNA replication and cell division. High expression of beta-tubulin III, a microtubule subunit with low taxane binding affinity, appears to confer resistance to taxane therapy. High expression of thymidylate synthase, an enzyme that is important in purine synthesis and DNA replication, has been associated with decreased response to uracil antimetabolites, and may also be an important prognostic factor in patients receiving pemetrexed. The epidermal growth factor receptor (EGFR) is a cell- surface receptor with an intracellular tyrosine kinase domain that is thought to modulate numerous cellular functions that contribute to tumorigenicity, tumor invasiveness, and resistance to therapy. Recent clinical trials have demonstrated that treatment response to small-molecule and monoclonal antibody inhibitors of EGFR is greatest for patients who have a higher EGFR gene copy number. CONCLUSION: Several genetic, molecular, and histological markers may affect treatment response in patients with NSCLC. Evaluating patients for such markers is important not only for treatment efficacy, but also to improve safety and tolerability by avoiding exposure to treatments that are unlikely to produce significant benefits. Nearly all of the available information regarding the predictive value of these markers has been derived from retrospective studies. Prospective clinical trials are important to validate marker evaluation methodology and the prospective utility of biomarkers in clinical decision making.