Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists?
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Antineoplastic Agents↗
Biomedical subjects
Scot C Remick
Publications and source records attributed to Scot C Remick.
Model-free parameters from dynamic contrast-enhanced-MRI: sensitivity to EES volume fraction and bolus timing.
PURPOSE: To quantify the unknown relative sensitivities of semiquantitative measures from dynamic contrast-enhanced (DCE) MRI to variations in the volume fraction V(e) of the extravascular extracellular space (EES), and the duration of the contrast injection. MATERIALS AND METHODS: Tissue-uptake curves were simulated across various values of F, PS, V(e), and bolus timings, with and without additive noise and at different image reacquisition rates. From each, the peak of the first derivative (G(peak)), the total uptake after the rapid first phase (CE), and the IAUC were calculated and plotted against F for each experimental condition. Relationships between each measure and the corresponding quantitative measure K(trans) were also examined, particularly for linearity. RESULTS: The highest sensitivity to flow was achieved for shorter bolus timings for G(peak), CE, and IAUC. G(peak) and IAUC were most linearly related to K(trans). The sensitivity to V(e) was lowest for G(peak), followed by IAUC and CE. Long sampling intervals resulted in severe underestimation of G(peak), while IAUC was unaffected provided that the limits of integration were properly applied. G(peak) could not be properly calculated in the presence of noise without a prior smoothing of the acquired curves, while IAUC was again unaffected by noise. CONCLUSION: G(peak) and IAUC are both useful model-free analogs of blood flow (i.e., K(trans)) for pre- and posttreatment comparisons. G(peak) may be the better choice in cases where larger changes in V(e) are likely, but only if sufficient noise reduction and fast image sampling are applied. If V(e) is expected to remain stable, IAUC is superior to G(peak) by virtue of its stability in the face of noise and more reliable estimation over a wider range of sampling rates.
Contrast Media↗
Drug insight: vascular disrupting agents and angiogenesis--novel approaches for drug delivery.
Vascular disrupting agents (VDAs), or endothelial disrupting agents, attempt to exploit the vascular endothelium that supplies rapidly dividing neoplasms. Unlike antiangiogenesis agents (e.g. the monoclonal antibody bevacizumab; and tyrosine kinase inhibitors sorafenib and sunitinib) that disrupt endothelial cell survival mechanisms and the development of a new tumor blood supply, VDAs are designed to disrupt the already established abnormal vasculature that supports tumors, by targeting their dysmorphic endothelial cells. Tumor vascular endothelium is characterized by its increased permeability, abnormal morphology, disorganized vascular networks, and variable density. VDAs induce rapid shutdown of tumor blood supply, causing subsequent tumor death from hypoxia and nutrient deprivation. The safety profile of this class of compounds is more indicative of agents that are indeed 'vascularly' active. For example, VDAs can cause: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. Despite these cardiovascular concerns some patients have benefited from VDAs in early clinical trials. Further drug development of VDAs must include the combination of these agents with other novel biological agents, cytotoxic chemotherapy, and radiotherapy. Close monitoring of patients receiving VDAs for any cardiovascular toxicity is imperative.
Angiogenesis Inhibitors↗
Challenges and opportunities for treatment and research of AIDS-related malignancies in Africa.
PURPOSE OF REVIEW: Following our review of AIDS-associated cancer in developing nations in 2004, we sought to update recent publications and review data on the challenges and opportunities for the treatment and research of AIDS malignancies in Africa. RECENT FINDINGS: It is apparent that the burden of AIDS-related malignancies and other virus-associated tumors is significant and increasing in Africa. Several recent studies report findings on conjunctival squamous cell carcinoma and there is a report that Hodgkin's disease, a non-AIDS-defining neoplasm, is increasing in incidence. International collaborative partnerships dedicated to AIDS malignancies in developing countries are feasible and invaluable for clinical strategies to address this aspect of the pandemic. A departure point is the ongoing work of the East Africa - Case Western Reserve University Collaboration in AIDS malignancies. SUMMARY: The burden of neoplastic complications of HIV infection and endemic virus-associated tumors are assuming increasing significance in Africa. There is a need to develop nonmyelotoxic therapies and approaches that are hypothesis-driven and pathogenesis-based. The scarcity and shortages in this region demand that our scientific and therapeutic strategies are both suitable and pragmatic for testing in this setting. It is also imperative that African investigators lead us in this important endeavor.
Africa↗
Novel Phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416.
PURPOSE: To determine the biological modulatory dose of SU5416, we employed a novel trial design, where "dose de-escalation" was based on demonstrable biological changes observed at the maximum tolerated dose. If such an effect was shown, dose de-escalation to a predefined dose level would occur to determine if the lower dose exhibited the same amount of pharmacodynamic effect as the higher dose. EXPERIMENTAL DESIGN: Ten patients with advanced solid tumors were enrolled at each dose level. One of the following pharmacodynamic effects was considered significant: (a) a 35% decrease in microvessel density in sequential tumor biopsies and (b) a 35% decrease in blood flow within tumor as assessed by dynamic contrast-enhanced magnetic resonance imaging. In addition, soluble E-selectin, soluble intercellular adhesion molecule, soluble vascular cell adhesion molecule, and plasma vascular endothelial growth factor were measured sequentially. RESULTS: Nineteen patients were enrolled. Sequential tumor biopsies in all evaluable patients showed an increase in microvessel density. Only one patient met the intended pharmacodynamic end point of >35% reduction in blood flow. There was a significant increase in both soluble E-selectin and soluble intercellular adhesion molecule levels pretreatment versus levels at the time of removal of patients from study (P = 0.04 and P = 0.0007, respectively). Levels of serum fibrinogen rose with therapy. There was a trend toward increase in plasma vascular endothelial growth factor levels. CONCLUSION: SU5416 does not result in decreased blood flow in tumors or a decrease in microvessel density. This corresponds to the lack of clinical activity seen with this agent. Our clinical trial design termed dose de-escalation is a novel approach to determine the in vivo biological effects of targeted therapies in cancer patients.
Adult↗
Randomized phase II trial of different schedules of administration of rebeccamycin analogue as second line therapy in non-small cell lung cancer.
Rebeccamcyin analogue (RA) is an antitumor antibiotic that results in DNA intercalation and topoisomerase I and II inhibition. Phase I trials of the daily x 5 schedule and once every 3 week schedule have been completed. Antitumor activity was observed during the phase I trials. The purpose of this study is to primarily determine the response rate of 2 different schedules of administration of RA in patients with advanced non-small cell lung cancer (NSCLC) who had progressed on one prior chemotherapy regimen. Secondary endpoints were median and 1-year survival rates. A two-stage Simon design was employed for both arms of the study. Patients were randomly assigned to either of two RA treatment schedules of 500 mg/m(2) as a 1 hr infusion repeated every 3 weeks (Arm A) or 140 mg/m(2)/day x 5 days repeated every 3 weeks (Arm B). Forty-two patients were randomized. No confirmed objective responses were seen. Stable disease was seen in 52% of patients on arm A and 37% on arm B. Median survival and 1 year survival rates were 5.6 months and 33.3% for arm A, 9.7 months and 42.1% for arm B respectively. Cox regression model demonstrated increased risk of death in patients younger than the age of 61 and for patients treated on arm A. RA failed to demonstrate a significant response rate in this disease setting, although the proportion of patients with stable disease and 1-year survival were encouraging and similar to other published studies of approved single agents for second-line therapy of NSCLC.
Adult↗
Promising systemic therapy for renal cell carcinoma.
In the United States, advanced kidney cancer accounts for over 12,000 deaths each year. Immunotherapy with either interferon or interleukin-2 (IL-2) has been the standard of care for over two decades. High-dose IL-2 can apparently cure 10% to 15% of patients treated, but due to the required inpatient care and the attendant toxicities, it is only administered to less than 1,000 patients per year in the United States (Chiron, personal communication). Interferon is a less active agent than IL-2 but it has still been shown to be superior to therapy with either megesterol or vinblastine. Interferon typically results in very few long-term responses and is given to most patients with metastatic kidney cancer. Median survival after interferon therapy is dependent on risk group but is typically 12 to 15 months. Thus, new therapies are urgently needed in this refractory disease. Novel compounds currently being tested in clinical trials are showing promise in advanced kidney cancer. The molecular targets of these drugs include interfering with the vascular endothelial growth factor receptors or the raf kinase pathway, angiogenesis inhibition, and antimicrotubule agents. A review of the preclinical and early clinical development of some of these novel compounds will be discussed.
Animals↗
Novel vascular targeting/disrupting agents: combretastatin A4 phosphate and related compounds.
Novel anticancer compounds are being developed that attempt to exploit the unique properties of the vascular endothelium, which supplies rapidly dividing neoplasms. The goal of these vascular targeting agents (VTAs) or endothelial disrupting agents is to cause rapid shutdown of tumor blood supply with subsequent tumor death from hypoxia and nutrient deprivation. VTAs are classified into two broad categories: biologic therapies or small molecule compounds. A variety of VTAs are in early clinical development. These agents have demonstrated clinical activity in phase I trials and are being evaluated with cytotoxic chemotherapy and radiotherapy.
Antineoplastic Agents, Phytogenic↗
Capacity building for the clinical investigation of AIDS malignancy in East Africa.
PURPOSE: To build capacity in the resource-poor setting to support the clinical investigation and treatment of AIDS-related malignancies in a region of the world hardest hit by the AIDS pandemic. METHODS: An initial MEDLINE database search for international collaborative partnerships dedicated to AIDS malignancies in developing countries failed to identify any leads. This search prompted us to report progress on our collaboration in this aspect of the epidemic. Building on the formal Uganda-Case Western Reserve University (Case) Research Collaboration dating back to 1987, established NIH-supported centers of research excellence at Case, and expanding activities in Kenya, scientific and training initiatives, research capital amongst our institutions are emerging to sustain a international research enterprise focused on AIDS and other viral-related malignancies. RESULTS: A platform of clinical research trials with pragmatic design has been developed to further enhance clinical care and sustain training initiatives with partners in East Africa and the United States. An oral chemotherapy feasibility trial in AIDS lymphoma is near completion; a second lymphoma trial of byrostatin and vincristine is anticipated and a feasibility trial of indinavir for endemic Kaposi's sarcoma is planned. CONCLUSIONS: In the absence of published reports of evolving international partnerships dedicated to AIDS malignancy in resource constrained settings, we feel it important for such progress on similar or related international collaborative pursuits to be published. The success of this effort is realized by the long-term international commitment of the collaborating investigators and institutions to sustain this effort in keeping with ethical and NIH standards for the conduct of research; the provision of formal training of investigators and research personnel on clinical problems our East African partners are faced with in practice and the development of pragmatic clinical trials and therapeutic intervention to facilitate technology transfer and enhance clinical practice.
Acquired Immunodeficiency Syndrome↗
Cardiovascular safety profile of combretastatin a4 phosphate in a single-dose phase I study in patients with advanced cancer.
PURPOSE: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. EXPERIMENTAL DESIGN: CA4P was administered in a dose-escalating fashion starting at 18 mg/m(2) i.v. every 21 days, and the maximal dosage was 90 mg/m(2). Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett's formula QTc = QT/(R-R interval)(1/2), and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and C(max) versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. RESULTS: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. CONCLUSIONS: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.
Adult↗
A medical oncologist's approach to immunotherapy for advanced renal tumors: is nephrectomy indicated?
Metastatic renal cell carcinoma is highly resistant to systemic therapy. Although interleukin-2 and interferon remain the most active agents for this disease, long-term survival rates remain poor. Two phase 3 trials, European Organization Research and Treatment of Cancer 30947 and Southwest Oncology Group 8949, have demonstrated a survival benefit of nephrectomy followed by interferon versus interferon alone in patients having an excellent performance status (PS 0 and 1). Removal of the primary tumor followed by interferon is not recommended for patients with a moderate or poor PS (PS 2-4). Even with this aggressive approach, most patients eventually will die from their kidney cancer; therefore, every patient with metastatic disease should be considered for enrollment into clinical trials.
Antineoplastic Agents↗
Surrogate markers in oncology practice and anticancer drug development: lessons learned from antiretroviral therapy?
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Anti-Retroviral Agents↗
AIDS-associated cancer in developing nations.
PURPOSE OF REVIEW: With the emergence of the highly active antiretroviral therapy era, it is apparent that the incidence of Kaposi sarcoma, in particular, and lymphoma in patients with AIDS is declining, especially in regions of the world where these regimens are routinely available. The burden of HIV infection and AIDS is greatest in the developing world, and no doubt neoplastic complications are increasingly encountered. The purpose of this review is to highlight recent developments of this aspect of the AIDS epidemic in the developing world. RECENT FINDINGS: It was readily apparent that the incidence of Kaposi sarcoma sharply increased after the onset of the AIDS epidemic in developing countries. By the end of the second decade of the epidemic, non-Hodgkin lymphoma is increasing in incidence and the natural history of Burkitt lymphoma is evolving in the backdrop of HIV infection as well. Cervical cancer is the most common cancer in women in many developing countries, yet the true impact of HIV infection on the development of this neoplasm is not fully understood. Squamous cell carcinoma of the conjunctiva appears to be a unique AIDS-associated neoplasm that is encountered in sub-Saharan Africa as well. Finally, although the epidemiologic and clinicopathologic features for many AIDS-associated neoplasms are well characterized in developing regions of the world, there is a paucity of data on the therapeutic approach to these tumors in this setting. SUMMARY: It is apparent that as the AIDS pandemic proceeds, the burden of neoplastic diseases is increasing in developing nations. Current therapeutic approaches are not well documented. Pragmatic prevention and therapeutic interventions suitable for the resource-constrained setting are clearly needed.
Acquired Immunodeficiency Syndrome↗
A Phase II trial of fixed dose rate gemcitabine in patients with advanced biliary tree carcinoma.
Gemcitabine is a commonly used chemotherapy for biliary tree carcinomas, achieving response rates of 10% to 60%. Preclinical studies indicate that fixed dose rate infusion optimizes accumulation of gemcitabine triphosphate and may enhance the clinical activity of gemcitabine. We conducted a phase II study of fixed dose rate gemcitabine in 15 chemotherapy-naive patients with advanced cholangiocarcinoma and gallbladder carcinoma. Gemcitabine was administered at a dose of 1500 mg/m2 over 150 minutes weekly for 3 weeks every 28 days. Fourteen patients were evaluable for response. No complete or partial responses were observed. Two patients (13%) had stable disease lasting a median of 9 weeks. The median time to progression was 9 weeks; median survival was 20 weeks. There was considerable grade 3/4 hematologic toxicity, including neutropenia in 49% of patients, leukopenia in 40%, anemia in 27%, and thrombocytopenia in 27%. Grade 3/4 nonhematologic toxicities were minimal. We conclude that fixed dose rate gemcitabine results in significant myelosuppression and has minimal activity in patients with biliary tree carcinoma.
Adult↗
Novel agents for the treatment of advanced kidney cancer.
Advanced kidney cancer accounts for over 12,000 deaths in the United States each year. Immunotherapy, typically interleukin-2 or interferon-alpha, have been the mainstay of treatment. Response rates are low for these immune-based treatments, and most patients with advanced kidney cancer succumb to their disease. There are several novel agents currently in clinical trials that show promise in this refractory disease. These compounds include antiangiogenic agents, raf kinase pathway inhibitors, and novel antimicrotubule agents. This review discusses some of the agents currently being explored for the treatment of advanced kidney cancer.
Angiogenesis Inhibitors↗
Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies.
PURPOSE: Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine. EXPERIMENTAL DESIGN: We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled. RESULTS: The dose-limiting toxicity was myalgia. The MTD and recommended Phase II dose of bryostatin 1 was 50 microg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting > or =6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h. CONCLUSIONS: Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted.
Adult↗
Dose-escalating and pharmacological study of oxaliplatin in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study.
PURPOSE: This study was undertaken to determine the toxicities, pharmacokinetics, and maximum tolerated doses of oxaliplatin in patients with renal impairment and to develop formal guidelines for oxaliplatin dosing in this patient population. PATIENTS AND METHODS: Thirty-seven adult cancer patients with variable renal function received intravenous oxaliplatin at 60 to 130 mg/m2 every 3 weeks. Patients were stratified by 24-hour creatinine clearance (CrCL) into four cohorts: group A (controls, CrCL > or =60 mL/min), group B (mild dysfunction, CrCL 40 to 59 mL/min), group C (moderate dysfunction, CrCL 20 to 39 mL/min), and group D (severe dysfunction, CrCL <20 mL/min). Doses were escalated in cohorts of three patients, and urine and plasma ultrafiltrates were assayed for platinum concentrations. RESULTS: No dose-limiting toxicities were observed in any patient group during the first cycle of therapy. Escalation of oxaliplatin to the maximum dose of 130 mg/m2 was well tolerated in all patient groups with a CrCL > or =20 mL/min (groups A, B, and C). Pharmacokinetic analysis showed that patients with decreased CrCL had a corresponding decrease in the clearance of plasma ultrafiltrable platinum (r2 = 0.765). However, oxaliplatin-induced side effects were not more common or severe in patients with mild to moderate renal dysfunction, despite the decrease in ultrafiltrable platinum clearance. CONCLUSION: Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.
Adult↗
Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group.
Oxaliplatin, which was recently approved by the US Food and Drug Administration for the treatment of advanced colorectal cancer, is often administered to patients with altered liver function caused by hepatic metastases. Because of the absence of data on the clearance of oxaliplatin in patients with liver dysfunction, and to develop dosing recommendations for the safe use of oxaliplatin in this clinical setting, the Organ Dysfunction Working Group of the National Cancer Institute performed a phase I and pharmacokinetic trial of this drug in patients displaying a wide range of liver function abnormalities. Sixty patients grouped into five classes of liver function were enrolled in this study, including a 12-patient control group with normal liver function, 15 patients with "mild," 16 patients with "moderate," and 16 with "severe" liver dysfunction, as well as one patient who had undergone liver transplantation. The patients had a median age of 62 years and a Eastern Cooperative Oncology Group performance status of 0. All patients had received prior systemic chemotherapy, and 70% had a diagnosis of a gastrointestinal malignancy. The control patients were treated with 130 mg/m(2) oxaliplatin intravenously every 21 days; the starting doses for patients with mild, moderate, or severe liver dysfunction or post-liver transplantation were 105, 80, or 60 mg/m(2), respectively. Cohorts of three or more patients were escalated from these starting doses to 130 mg/m(2) if dose-limiting toxicities were not observed, and pharmacokinetic evaluations were performed at each dose level for every category of liver dysfunction. We found that oxaliplatin was well tolerated at its recommended dose and schedule of 130 mg/m(2) every 21 days in patients with all levels of liver dysfunction, and that there was no apparent alteration in the clearance of either total or ultrafilterable platinum species from plasma, even in patients with severe hepatic functional abnormalities.
Antineoplastic Agents↗