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Journal of Clinical Oncology, Vol 24, No 10 (April 1), 2006: pp. 1485-1488 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.8801
Promise of New Vascular-Disrupting Agents Balanced With Cardiac Toxicity: Is It Time for Oncologists to Get to Know Their Cardiologists?Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH
Division of Cardiology, Department of Medicine, CASE School of Medicine, Cleveland, OH
Departments of Radiology and Biomedical Engineering, CASE School of Medicine, Cleveland, OH
Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University School of Medicine, Developmental Therapeutics Program, CASE Comprehensive Cancer Center, University Hospitals of Cleveland, Cleveland, OH In this issue of the Journal of Clinical Oncology, Beerepoot et al1 report the results of their phase I trial of ZD6126, an interesting agent among the first generation of tubulin-binding compounds that function as vascular targeting or, preferably, vascular disrupting agents (VDAs). Representative VDAs include ZD6126, combretastatin A4 phosphate (CA4P), TZT-1027, AVE8062, ABT-751, and MN-029, all of which bind tubulin; exherin (AFH-1), which targets cell adhesion; and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which targets autocrine endothelial regulatory cascades. Recently, VDAs have made the transition from preclinical in vivo laboratory experiments to early-phase clinical trials in humans. Unlike the more well-known antiangiogenic agents, such as the humanized monoclonal antibody bevacizumab and the small molecule tyrosine kinase inhibitors sorafenib (BAY 43-9006) and sunitinib (SU11248) that disrupt endothelial cell survival mechanisms and the recruitment and development of a new tumor blood supply, VDAs are designed to disrupt the established abnormal vasculature that feeds tumors by targeting their dysmorphic endothelial cells. Tumor endothelium is primarily reliant on a tubulin cytoskeletal network to maintain functional integrity. As more experience with this class of compounds is gained in early phase I trials, time-honored cytotoxicity profiles of myelosuppression, stomatitis/mucositis, and alopecia are giving way to safety profiles that are more indicative of vascularly active agents: acute coronary and other thrombophlebitic syndromes; alterations in blood pressure, heart rate, and ventricular conduction; transient flush and hot flashes; neuropathy; and tumor pain. We will discuss the clinical and anticancer drug development significance of elevated cardiac enzymes; comment on the utility of biomarker or pharmacodynamic correlates of drug effects, especially circulating endothelial cells and noninvasive imaging of tumor blood flow; and provide cautionary but enthusiastic commitment to further define the utility of VDAs in the contemporary anticancer therapeutic armamentarium. Jeremias and Gibson2 reviewed etiologies other than acute coronary syndrome for elevated cardiac biomarkers, especially elevated cardiac troponin (CPK-MB fraction, as reported by Beerepoot et al), which is highly sensitive for myocardial necrosis. Nonatherosclerotic, nonthrombotic etiologies of elevated cardiac troponin levels relevant to the development of VDAs include demand ischemia, myocardial ischemia, direct myocardial injury, and myocardial strain.2 An example of demand ischemia is hypotension, which leads to decreased perfusion pressure and global myocardial ischemia. Myocardial ischemia may result from nonatherosclerotic causes such as coronary and microvascular vasoconstriction or vasospasm that, if prolonged, can lead to myocardial necrosis. Anticancer therapy can be detrimental to myocardium either directly, as described, or indirectly via inflammatory myopericarditis or right ventricular strain secondary to pulmonary hypertension or pulmonary thromboembolism (the latter of which was a dose-limiting toxicity at the 28 mg/m2/wk in the ZD6126 trial) with subsequent elevations in cardiac biomarkers. In addition, declines in left ventricular ejection fraction and myocardial infarction were also encountered during dose escalation of ZD6126. The adverse effect profile for many of the VDAs, reviewed at the 41st Annual Meeting of the American Society of Clinical Oncology (Orlando, FL, May 13-18, 2005) and by Remick et al3 and Cooney et al,4 include many of these same cardiovascular toxicities. The experience of ZD6126 adds to this growing list; asymptomatic CPK-MB release occurred across most dosages (7 to 20 mg/m2/wk, the maximum tolerated dose), and there was no apparent correlation of CPK-MB level and drug exposure. The clinical significance of an asymptomatic cardiac biomarker release must be carefully considered. Given the limited pharmacodynamic analysis, it is suggestive that neither a threshold (eg, maximum concentration) nor an exposure (eg, area under the concentration time curve) effect was identified with this agent. Either would no doubt better inform the optimal administration of the drug. Any cardiac enzyme release is indicative of myocardial necrosis, and it will be important as we develop new agents with cardiovascular adverse effects to precisely redefine the dose-limiting toxicity definitions regarding asymptomatic cardiac biomarker release. The Common Terminology Criteria for Adverse Events (CTCAE) do not specifically reference grades of CPK-MB fraction release, although troponin levels are graded. CPK-MB fractions that exceed 10 U/L are associated with large infarct size, and there is a direct correlation between size of troponin release and prognosis following myocardial infarction, even in patients found to have noncritical coronary disease at angiography.5 The clinically relevant thresholds for anticancer drug development are not known. As this agent, or any other with similar toxicity, moves forward in the clinic, the cumulative effects of any dose and cardiac biomarker release must be followed closely. In addition to traditional cardiac biomarkers, newer biomarkers such as brain natriuretic peptide, C-reactive protein, and interleukin-6 may increase during therapy with VDAs and similar compounds. Future clinical studies may need to consider measurement of these biomarkers, because they may be indicative of potential myocardial injury before myocardial necrosis. One biomarker that shows particular promise is ischemia-modified albumin; its serum elevation may precede that of conventional biomarkers and may occur during the earliest stages of myocardial ischemia in the absence of overt infarction and necrosis.6 The use of circulating endothelial cells (CECs) as biomarkers for biologic response to VDAs and antiangiogenic agents is expanding, though interpretation of this measurement is still somewhat uncertain. Mutin et al7 first proposed that CECs could be used as markers for endothelial injury after observing prominent increases in CECs in patients with acute myocardial infarction compared with those with noncoronary chest pain. Monestroli et al8 proposed that CECs could be used as a biomarker for antiangiogenesis when they demonstrated an increase in CECs in response to the administration of endostatin, an antiangiogenic agent, in mice bearing human lymphoma. These authors hypothesized a concomitant increase in the number of CECs occurs as the vasculature is disrupted. Others have demonstrated that the baseline level of CECs is increased in patients with cancer.9 There are, however, a number of confounding issues. For example, CECs are comprised of at least two cell populations: bone marrow-derived circulating endothelial progenitor cells (EPCs), such as CD146+, CD45– and CD133+, and mature CECs, such as CD146+, CD45–, and CD133–, which are believed to derive from existing vasculature.10 Schuch et al11 have proposed that EPCs increase in response to angiogenic factors and decrease in response to antiangiogenic agents, based on their observation that the vascular endothelial growth factor (VEGF) –induced increase in EPCs in mice is blocked by concurrent endostatin administration. Others have extended these observations by correlating EPC levels with genetically determined angiogenic potential and by demonstrating that circulating EPCs decrease in response to effective concentrations of antiangiogenic agents in preclinical tumor models.10 Several antiangiogenic agents, including endostatin, exhibit a biphasic, U-shaped dose-response curve, which is paralleled by levels of total CECs12; the increase in CECs at higher, less effective doses of endostatin may reflect shedding of mature endothelial cells from the vasculature, as occurs transiently in patients during the first month of endostatin treatment.13 Regardless, these observations suggest that the use of CECs as biomarkers of antiangiogenic or antivascular effect might be optimized by careful dissection of mature CEC and EPC contributions. The effect of VDAs on CECs has been less extensively studied than that of antiangiogenic agents, but interesting results have been reported. For example, Yee et al14 demonstrated a decrease in the number of total CECs in response to the VDA ABT-751 in patients with hematologic malignancies. Recently, Beaudry et al15 reported an increase in both EPCs and mature CECs in non–tumor-bearing mice given VEGF, which was inhibited by the VEGF receptor-2 inhibitor ZD6474. However, in mice bearing Lewis lung carcinoma, ZD6474 caused a dose-dependent increase in mature CECs accompanied by a decrease in tumor microvessel density and volume but no change in circulating EPCs. Using the same model, the VDA ZD6126 induced an even more dramatic increase in mature CECs, accompanied by a modest increase in EPCs. Although several hypotheses may be raised to account for these differences, these data again demonstrate the need for additional studies examining the significance of changes in CECs and EPCs in preclinical models and in patients treated with antineoplastic regimens. In addition, there are studies linking decreased EPC levels with an increased risk of cardiovascular disease.16 The data of Beerepoot et al must be carefully considered and regarded as exploratory. CEC levels were measured via flow cytometry using CD146+ as a marker for total CECs (ie, no differentiation between mature CECs and EPCs). There was no apparent correlation between increased CECs and ZD6126 dose, peak plasma concentration, or net drug exposure. At best, a potential temporal association with drug administration was noted, which could represent the natural history of patients with advanced cancer, and not a true drug effect. The most consistent pharmacodynamic measure of drug effect that has been clearly reported for many of the VDAs is demonstrable change in tumor blood flow and perfusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) strategies. Tumors are visualized before drug administration by radiologic imaging, and perfusion changes are assessed by DCE-MRI at baseline and at different time periods after drug administration. The amount of signal amplitude change within the DCE-MRI image as a result of contrast agent (eg, gadolinium diethylenetriaminepentaacetate) administration is measured as the initial area under the uptake versus time curve (IAUC) and reflects the tumor blood flow, the surface area permeability product, and the fraction of interstitial space perfused.17 In mice bearing CD38 adenocarcinoma, increasing doses of ZD6126 led to statistically significant decreases in IAUC only after administration of ZD6126 in tumors visualized with DCE-MRI techniques, and these differences were not observed in muscle or spleen.18 In five of six patients receiving ZD6126, IAUC decreased 6 hours after administration of ZD6126.19 In six of seven patients receiving CA4P, statistically significant decreases were observed in gradient peak only after the administration of CA4P.20 Eight of 16 patients receiving DMXAA experienced up to a 66% reduction of tumor blood flow up to 24 hours after DMXAA infusion.21 Taken together, these results suggest that VDAs decrease perfusion of tumors, firmly establish proof-of-principle of drug mechanism, and, when combined with the clinical safety profile that is emerging in the clinic, suggest that other vascular compartments may be affected as well. What is less clear is the utility of DCE-MRI to guide our use of these agents in the clinic. Recently, changes in tumor blood flow did correlate with tumor response in a small number of patients with advanced renal cancer treated with sorafenib.22 In summary, Beerepoot et al are to be congratulated for their pursuit and reporting of the phase I trial of ZD6126, which no doubt presented unique challenges to their team. As we develop a variety of new anticancer therapies with extended or different spectrums of clinical toxicity, oncologists must engage our colleagues from different disciplines to better understand the many anticancer early phase drug development issues that emerge. Although there is the hint of meaningful clinical activity (not observed in this phase I study) for many of these agents, we must determine the best way to safeguard our patients as we develop novel anticancer agents in the clinic.23-25 The mechanism of action of VDAs (inducing central necrosis in tumor masses) provides a strong rationale for combination therapy with other drugs and modalities, especially radiation. Given the hypothesis of Jain26 on vascular normalization and given the emerging clinical data on the impact of adding bevacizumab to platforms of cytotoxic chemotherapy across a spectrum of solid tumors, antivascular/antiangiogenic therapies will be integrated into most, if not all, solid tumor treatment strategies in the not-too-distant future. Now is the time, at least with agents of the VDA drug class, for oncologists to engage cardiologists in the development of these interesting compounds. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Author Contributions
REFERENCES
1. Beerepoot LV, Radema SA, Witteveen EO, et al: Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24:1491-1498, 2006 2. Jeremias A, Gibson CM: Narrative review: Alternative causes for elevated cardiac troponin levels when acute coronary syndromes are excluded. Ann Intern Med 142:786-791, 2005 3. Remick SC, Cooney MM, Tolcher AW, et al: Current development of vascular targeting agents in: ASCO Educational Book. Alexandria, VA, American Society of Clinical Oncology, 2005, pp 212-216 4. Cooney MM, Ortiz J, Bukowski RM, et al: Novel vascular targeting/ disrupting agents: Combretastatin A4 phosphate and related compounds. Curr Oncol Rep 7:90-95, 2005[Medline] 5. Dokainish H, Pillai M, Murphy SA, et al: Prognostic implications of elevated troponin in patients with suspected acute coronary syndrome but no critical epicardial coronary disease: A TACTICS-TIMI-18 substudy. J Am Coll Cardiol 45:19-24, 2005 6. Wu AH: Markers for early detection of cardiac diseases. Scand J Clin Lab Invest Suppl 240:112-121, 2005[Medline] 7. Mutin M, Canavy I, Blann A, et al: Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 9:2951-2958, 1999 8. Monestroli S, Mancuso P, Burlini A, et al: Kinetics and viability of circulating endothelial cells as surrogate angiogenesis marker in an animal model of human lymphoma. Cancer Res 61:4341-4344, 2001 9. Mancuso P, Burlini A, Pruneri G, et al: Resting and activated endothelial cells are increased in the peripheral blood of cancer patients. Blood 97:3658-3661, 2001 10. Shaked Y, Bertolini F, Man S, et al: Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7:101-111, 2005[Medline] 11. Schuch G, Heymach JV, Nomi M, et al: Endostatin inhibits the vascular endothelial growth factor-induced mobilization of endothelial progenitor cells. Cancer Res 63:8345-8350, 2003 12. Celik I, Sürücü O, Dietz C, et al: Therapeutic efficacy of endostatin exhibits a biphasic dose response curve. Cancer Res 65:11044-11050, 2005 13. Heymach JV, Kulke MH, Fuchs S, et al: Circulating endothelial cells as a surrogate marker of antiangiogenic activity in patients treated with endostatin. Proc Am Soc Clin Oncol 22:2004, 2003 14. Yee KW, Hagey A, Vesrtovsek S, et al: Phase I study of ABT-751, a novel microtubule inhibitor, in patients with hematologic malignancies. Clin Cancer Res 11:6615-6624, 2005 15. Beaudry P, Force J, Naumov GN, et al: Differential effects of vascular endothelial growth factor receptor-2 inhibitor ZD6474 on circulating endothelial progenitors and mature circulating endothelial cells: Implications for use as a surrogate marker of antiangiogenic activity. Clin Cancer Res 11:3514-3522, 2005 16. Hill JM, Zalos G, Halcox JP, et al: Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348:593-600, 2003 17. Evelhoch JL: Key factors in the acquisition of contrast kinetic data for oncology. J Magn Reson Imag 10:254-259, 1999[CrossRef][Medline] 18. Evelhoch JL, LoRusso PM, He Z, et al: Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 10:3650-3657, 2004 19. DelProposto Z, LoRusso PM, Latif Z, et al: MRI evaluation of the effects of the vascular-targeting agent ZD6126 on tumor vasculature. Proc Am Soc Clin Oncol 20:111a, 2002 (abstract nos. 440) 20. Dowlati A, Robertson K, Cooney M, et al: A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin A-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer. Cancer Res 62:3408-3416, 2002 21. Galbraith SM, Rustin GJS, Lodge MA, et al: Effects of 5,6-dimethylxanthenone-4-acetic acid on tumor microcirculation assessed by dynamic contrast-enhanced magnetic resonance imaging. J Clin Oncol 20:3826-3840, 2002 22. O'Dwyer PJ, Rosen M, Gallagher M, et al: Pharmacodynamic study of BAY 43-9006 in patients with metastatic renal cell carcinoma. Proc Am Soc Clin Oncol 23:193s, 2005 23. Cooney MM, Radivoyevitch T, Dowlati A, et al: Cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a single-dose phase I study in patients with advanced cancer. Clin Cancer Res 10:96-100, 2004 24. Varterasian M, Fingert H, Agin M, et al: Consideration of QT/QTc interval data in a phase I study in patients with advanced cancer. Clin Cancer Res 10:5967-5968, 2004 25. Cooney M, Radivoyevitch T, Dowlati A, et al: Invited Letter to the Editor in response to Varterasian, M., et al: Letter / commentary on the cardiovascular safety profile of combretastatin A4 phosphate in a single-dose phase I trial in patients with advanced cancer [Clin Cancer Res 10:96-100, 2004]. Clin Cancer Res 10:5968-5969, 2004 26. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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