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Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway (VSP). This prospective, single center, cohort study characterized ambulatory blood pressure (BP) monitoring (ABPM) as an early pharmacodynamic biomarker of VSP inhibition by sorafenib.
Fifty-four normotensive advanced cancer patients underwent 24-hour ABPM prior to and between days 6 and 10 of sorafenib therapy. After BP changes were detected among the first cohort within 10 days, ABPM was performed during the first 24 hours of treatment for the second cohort.
For the entire patient population the BP increase (mean systolic +10.8 mmHg [95% CI, 8.6 to 13.0], range −5.2 to +28.7 mmHg; mean diastolic +8.0 mmHg [95% CI, 6.3 to 9.7], range −4.4 to +27.1mmHg) was detected between days 6 and 10 (P <0.0001 for both) and plateaued thereafter. Variability in BP change did not associate with: age, body size, sex, self-reported race, baseline BP, or steady state sorafenib plasma concentrations. In the second cohort the BP elevation was detected during the first 24 hours (mean systolic +8.2 mmHg [95% CI, 5.0 to 11.3]; mean diastolic +6.5 mmHg [95% CI, 4.7 to 8.3] P <0.0001 for both).
ABPM detects the BP response to VSP inhibition by sorafenib during the first 24 hours of treatment. The magnitude of BP elevation is highly variable and unpredictable, but could be important in optimizing the therapeutic index of VSP inhibitor therapy.
Currently, three vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors: bevacizumab, sorafenib, and sunitinib, are approved for marketing for anticancer indications by the United States Food and Drug Administration (1–8). More agents in this class are in late stages of clinical development (9–11). Although the indications for these agents are expanding, little is known about their therapeutic index or how to dose them and provide supportive care for maximum safety and efficacy.
Hypertension is a mechanism-based toxicity of these agents. Mean systolic and diastolic blood pressure (BP) for cohorts of patients receiving VSP inhibitors increase with exposure to these drugs(12–14), and return to baseline with drug withdrawal(15). These observations suggest that blood pressure might be a pharmacodynamic biomarker of VSP inhibition that could determine which patients have received a subtherapeutic dose, and consequently will not benefit from the treatment, and those who might have received a supratherapeutic dose and are at unnecessary risk for systemic toxicities. Mean BP for groups of patients has been reported because even with standardized office or home measurements, the variability in measurement precludes conventional BP (16) as a pharmacodynamic biomarker for VSP inhibitors.
Ambulatory BP monitoring (ABPM) is a validated, qualified biomarker for antihypertensive drug development with several advantages over, and better accuracy than typical office measurements (17). BP data can be collected over the entire dosing interval. The mean of all measurements collected over 24 hours better correlates with long term clinical outcomes than a few office measurements. ABPM provides reduced measurement variability, and so trials require fewer patients, and placebos have been demonstrated to have negligible effects on mean ambulatory BP (18).
To assess ABPM as a pharmacodynamic marker of VSP inhibition we prospectively measured ambulatory BP in normotensive, advanced cancer patients to determine the time to development and magnitude of BP elevations caused by sorafenib. Unexpectedly, we found in the initial cohort of 29 patients that most developed BP elevations during the first 10 days of treatment. The measurement schedule was then modified for the second cohort to detect effects of sorafenib on BP during the first day of treatment. Additionally, we investigated the relationship between the known interindividual variability in sorafenib steady state plasma concentrations at the standard dose of 400 mg twice daily and the variability in the BP changes.
Oncologists recruited subjects at the University of Chicago Hospitals outpatient center. The first cohort (29 subjects) began in October 2004, and the second (25 subjects) began accrual in June 2005. Subjects with: solid cancers for which appropriate measures had failed or for which there was no known superior treatment, life expectancy ≥ 12 weeks, age ≥ 18 years, and ability to perform at least sedentary work (Eastern Cooperative Oncology Group Performance Status rating of 0 or 1) were eligible. Subjects had to have acceptable organ function by pre-specified laboratory measures and provide written, informed consent prior to baseline testing. Patients were excluded if pre-treatment BP was > 140/90 mmHg, if they had history of any arrhythmia other than paroxysmal atrial fibrillation, ≥ New York Heart Association Class II congestive heart failure or if they required more than one antihypertensive agent for any chronic cardiovascular disease management. Patients at risk for acute complications of hypertension were referred to cardiovascular medicine specialists for evaluation, fewer than 5 enrollees underwent such evaluations and these pre-study registration data were not collected. Patients with unstable conditions, untreated brain metastases, recent open surgical procedures, seizure disorders, or immune deficiency also were excluded. Treatment previously with VEGF signaling pathway inhibitors (eg. bevacizumab, sunitinib), or concurrently with other anticancer agents or erythropoiesis-stimulating agents was prohibited. The study protocol was approved by the Institutional Review Board of the Biological Sciences Division of the University of Chicago.
All subjects initially received sorafenib (Bayer, West Haven, Connecticut) 400 mg orally twice daily, with subsequent dosing adjusted for toxicity, as previously described(5). Subjects underwent clinical evaluations of cancer progression by computed tomographic imaging at least every 8 weeks, and remained on treatment until: sorafenib proved intolerable, clinical presentation was consistent with disease progression, or imaging findings met Response Evaluation Criteria in Solid Tumors for progressive disease(19).
Whether and when to administer antihypertensive therapy was determined by weekly standardized BP measurements collected according to published guidelines(16) with a device (Omron Healthcare, Bannockburn, Illinois) certified by the International Protocol(20). Briefly, these office-based measurement sessions entailed collection of 3 measurements separated by at least 3 minutes with attention to proper positioning of the patient, cuff size, and technique by a trained observer. The mean of 3 measurements meeting accuracy criteria was used for screening, toxicity grading, and management decisions. Patients with systolic BP ≥ 150 mmHg, diastolic BP ≥ 100 mmHg or ≥ 20 mmHg more than the baseline measurement had Grade 2 hypertension by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 1and were treated according to structured agent selection and dose titration. If a BP < 140/90 mmHg was not achieved with two agents maximally titrated over a 3-week period, the sorafenib was withheld until the goal BP was achieved, and restarted at a lower dose. Patients who developed other Grade 2 events (commonly including hand-foot skin reaction, diarrhea, and hypophosphatemia) had sorafenib withheld and dose adjusted accordingly.
This study was conducted under Investigational New Drug license 069913 held by the University of Chicago. Bayer, Inc. permitted cross-referencing of their data on file at the United States Food and Drug Administration, provided investigational sorafenib tablets, and performed measurement of plasma sorafenib concentrations in blinded fashion.
ABPM with an appropriately sized cuff (Oscar PowerPack2, SunTech Medical, Morrisville, North Carolina) was performed: at baseline (1–13 days prior to commencing treatment), when steady state plasma concentrations of sorafenib were first reached (between days 6–10 post treatment initiation), and at least once between days 34 and 71 post-treatment initiation. Subjects in the second cohort had an additional 24-hour session on the first day, during administration of the first 2 doses of sorafenib. Devices were programmed for patients' reported sleep schedules: daytime measurements collected every 10–15 minutes and nighttime every 45 minutes. For each subject, the unweighted mean of minimum 40 measurements that met device software parameters for quality control collected over 24 hours was used as a summary measure for all analyses. The intra-device measurement variability, tested repeatedly on a reference volunteer subject for 24-hour sessions throughout the study, was within 2.5 mmHg systolic and 2 mmHg diastolic.
Plasma samples were collected in sodium-heparinized tubes, centrifuged for 15 minutes immediately after collection at 4°C and stored at −80°C. Batched samples were shipped on dry ice within 8 months of collection to Northeast Bioanalytical Laboratories (Hamden, Connecticut), for determination of sorafenib concentration by HPLC/mass spectroscopy with 80% acetonitrile mobile phase(21). For subjects in the first cohort, the minimum measured plasma concentration of total sorafenib was determined from samples that were collected after at least 6 days of continuous sorafenib dosing, ≥ 16 hours after the previous dose, and prior to the next dose (subjects were instructed to hold their AM dose until arrival to the research center and 16 subjects had these samples available). For subjects in the second cohort, the minimum measured total sorafenib plasma concentration from all samples collected on days 8 and 9 was used (25 subjects).
Changes in BP were calculated by subtracting baseline values for each subject from each subsequent measurement session. The significance of these changes was determined by paired t-test, and correlated with baseline categorical variables (eg. sex) by two-sample t-tests. Pearson's correlation coefficient was used for determination of the associations among different continuous measurements (eg. change in BP and age). Correlation between change in BP and plasma sorafenib concentrations also entailed using an ordered logistic regression model where change in SBP was coded as 0 for < 5 mmHg (no detectable change), 1 for ≥ 5–19.9 mmHg (typical change), and 2 for ≥ 20 mmHg (high magnitude change), and for change in DBP as 0 for < 4 mmHg, 1 for ≥ 4– 14.9 mmHg, and 2 for ≥ 15 mmHg. Statistical significance was defined as P < 0.05. All statistical analyses were performed with Stata 10 (StataCorp LP, College Station, Texas).
Of 70 patients completing baseline evaluation and initiating sorafenib therapy, 54 (77%) had uninterrupted sorafenib dosing and BP measurements collected both at baseline and on or after day 6. In this advanced disease population 12 patients underwent the initial baseline BP measurement session but were deemed unevaluable because of disease complications interfering with treatment initiation and/or completion of the second BP measurement session. Two subjects failed to adhere to the treatment program and were deemed unevaluable. Two subjects required dose interruptions and did not have steady state plasma sorafenib concentrations at the day 6–10 BP measurement session. Characteristics of the 54 evaluable patients are summarized in Table 1.
All subjects were normotensive at baseline by standardized office measurements. When steady-state plasma sorafenib concentrations were first reached during days 6–10, the mean change in the 24-hour mean systolic BP was 10.8 mmHg [95% CI 8.6, 13.0; median = 9.4] and for diastolic BP it was 8.0 mmHg [6.3, 9.7; median = 7.3] (P < 0.0001 for both). BP appears to plateau subsequently (Figure 1 and Table 2). For the 25 subjects undergoing ABPM on Day 1, the mean change in the 24-hour mean systolic BP was 8.2 mmHg [5.0, 11.3; median = 7.0] and for diastolic BP it was 6.5 mmHg [4.7, 8.3; median = 5.8] (P < 0.0001 for both) (Table 2). Visits after Day 10 include fewer patients due to attrition from disease progression or inter-current serious adverse events. In addition, 14 subjects had active intervention to control the BP elevation safely during the interval between Day 10 and the subsequent measurement session (i.e. these patients met CTCAE v. 3.0 grade 2 or 3 hypertension criteria). This medically appropriate intervention was based on the weekly measurements and not the ambulatory measures. The introduction of antihypertensive therapy in some patients contributes, in part, to the population plateau effect after steady state concentrations were reached. Given the modest sample of patients, analyses of interindividual variability in BP response and association with various factors focus on the interval between baseline and steady state. During this time the only intervention for all participants was the oral administration of sorafenib at the same dose of 400 mg twice daily.
The magnitude of BP elevation varies among individuals when steady state plasma sorafenib concentrations are reached (Figure 2). Eight subjects had an elevation of systolic and diastolic BP nearly twice the mean change (SBP ≥ 20 mmHg and DBP ≥ 15 mmHg equating to a mean arterial BP of 16.7 mmHg) for the study population, while 14 subjects had BP elevations less than twice the threshold measurement variability of the devices (for SBP ≤ 5 mmHg and DBP ≤ 4 mmHg equating to a mean arterial BP of 4.3 mmHg) - essentially no elevation.
There was no significant association of the magnitude of change in systolic or diastolic BP with age, body mass index, sex, self-reported race (white vs. other), or tumor type (renal cell vs. other). All patients in this study had their baseline BP within the normal range with no more than one antihypertensive agent. Within this patient population, there was no positive correlation between the magnitude of the baseline BP measurement and the change in BP due to sorafenib exposure for 6–10 days (Figure 3). There also was no association with baseline renal function or presence/absence of antihypertensive therapy.
As no other readily measurable clinical variables accounted for variability in change in BP during initial sorafenib exposure, we hypothesized that the known pharmacokinetic variability of total plasma sorafenib concentrations(22) might correlate with variability in effects on BP. The relationship is complex (Figure 4), and to detect any direct correlation between sorafenib plasma concentrations and change in BP, an ordered logistic regression model was fit in addition to calculating the Pearson correlation coefficient. For the 41 subjects with minimum observed plasma specimen concentrations available, the change in BP was categorized as no detectable change, typical change, and high magnitude change (as described in Figure 2 and Methods). Odds ratios are expressed per one standard deviation increase in minimum concentration, i.e. per 2542 ng/mcL. For SBP, OR = 1.29 [95% CI = 0.63, 2.61], P = 0.49 and for DBP, OR = 1.22 [95% CI = 0.62, 2.43], P = 0.57. The Pearson correlation coefficients were 0.20 (p=0.21) and 0.19 (p=0.24), respectively. These data indicate that there is no direct relationship between the interindividual variability in sorafenib pharmacokinetics and variability in the change in BP due to exposure to sorafenib.
In this cohort of advanced cancer patients we have demonstrated that: 1) the time at which sorafenib-induced BP elevation is detectable is as early as the first day of therapy and more readily detected when steady state concentrations of sorafenib are first reached at approximately day 7, 2) the magnitude of this effect varies with several individuals (approximately 25%) having minimal BP change and approximately 15% of subjects having relatively dramatic elevations over the first week of treatment, and 3) this BP variability is not associated with the baseline blood pressure or the variability in total plasma concentrations of sorafenib with the standard starting dose of 400 mg twice daily.
BP elevations due to VSP inhibition were first demonstrated with sorafenib in a cohort of 20 subjects using structured office measurements over the typical clinical evaluation interval of 3 weeks(13). For another VSP inhibitor, sunitinib, detection at week 1 with home BP monitoring was recently reported (15). Using the more intensive measurement technique of ambulatory monitoring detects changes earlier in the treatment course and more reliably within individual subjects. In this investigation we did not have the opportunity to compare these two techniques contemporaneously. It will be useful to determine the minimum sampling of blood pressure measurements necessary for accurate assessment of a patient's individual BP response to VSP inhibitor therapy.
For safe management of normotensive patients receiving these drugs, these data suggest BP measurements should be performed no later than when drug steady-state plasma concentrations are first reached. The magnitude of BP elevation even for patients with normal BP is variable and unpredictable. Our findings of a rapid increase in BP with initial exposure to sorafenib are consistent with the hypothesis that VSP inhibition causes blockade of VEGF-mediated post-translational activation of endothelial nitric oxide synthase, leading to decreased nitric oxide production and increased vascular tone. As highlighted in studies of VSP inhibition in a rodent model of pancreatic cancer(23), a second, slower mechanism of BP elevation may develop from induction of endothelial cell apoptosis, leading to diminished production of numerous endothelium-derived vasodilatory factors and decreased microcapillary density in at least some organ-beds, causing increased resistance and pressure in larger vessels. Microscopic imaging of the adult mammalian vasculature during treatment with various VSP inhibitors (24, 25) demonstrates a clear role for VEGF in regulating endothelial cell survival in the non-tumor microvasculature. These imaging studies also demonstrate that loss of endothelial cell coverage of capillaries is reversible upon cessation of VSP inhibition. Two subjects in our investigation who had sorafenib withheld or the dose decreased for non-vascular toxicities had decreases in their BP (data not shown), and in a home BP monitoring study, when sunitinib had been withheld for two weeks BP decreased(15). The specific mechanism for this recovery is unclear, but the hypothesis that this represents restoration of microvascular flow and/or endothelial cell repopulation of capillaries is consistent with the time course of these events demonstrated in rodent experiments(25). Scientifically it would have been ideal to collect ambulatory BP measurements from patients upon failure of treatment to document the time course and magnitude of decline in the blood pressure off sorafenib but this was deemed an excessive request in this advanced solid tumor patient population. An ongoing trial2 examines off-treatment effect early in the course of sorafenib therapy.
Since this effect can be detected so early in the treatment course, it is appealing to think that the magnitude of change in BP could serve as a biomarker for VSP inhibitors and be used to guide treatment of various malignancies. But to determine how best to use this putative marker to individualize VSP inhibitor therapy requires answers to three questions:
1) Does variability in changes in BP on exposure to VSP inhibitors reflect pharmacokinetic or pharmacodynamic variability?
2) Does the magnitude of BP elevation mark exposure of the individual to differing degrees of VSP inhibition, differing degrees of endothelial cell apoptosis and endothelial cell reserve, or variability in the capacity of BP regulatory mechanisms to respond to the stress of VSP inhibition?
3) Does the magnitude of pharmacodynamic effects on the systemic vasculature directly reflect the effects on the tumor vasculature and tumor growth, survival, and spread?
Our study addresses the first question and our findings are consistent with the conclusion that variability in changes in BP due to VSP inhibition reflects pharmacodynamic variability. The variability in BP response is not associated with the known variability in total sorafenib concentrations in plasma. The BP variability may be better explained by: 1) a measure of free concentrations of sorafenib, 2) pharmacokinetic (PK) variability of an undetected metabolite of sorafenib (although sorafenib is the predominant molecule in plasma at steady state, and is a more potent inhibitor of the VSP than its detectable metabolites), or 3) physiologic and pharmacodynamic variability, for example increased sensitivity to eNOS down-regulation or diminished counter-regulatory BP lowering mechanisms.
Our study is limited by a number of issues. We had no control group or structured withdrawal of sorafenib in order to demonstrate definitively that the magnitude of BP elevation is directly related to sorafenib exposure and not other factors. A second issue is the flexibility in the scheduling of the BP measurement sessions (some as early as day 6 and others as late as day 11). The timing of the measurement within this interval did not associate with the magnitude of change in BP measured over the interval (data not shown). As this study was performed in a cohort of advanced solid tumor patients with various malignancies, there's no opportunity to determine fairly the relationship between BP changes and tumor response. Finally, we only measured total sorafenib plasma concentrations and theoretically, unbound concentrations of sorafenib (rather than the total free and protein-bound forms of drug as reported here) might better correlate with change in BP. This investigation determined BP-elevating effects only in patients receiving sorafenib, and though these findings might be true for all VEGF signaling pathway inhibitors, they remain to be confirmed for these other drugs.
As described above, these data suggest two important directions for future research regarding BP as a mechanism-based effect of VSP inhibition. As we and others have suggested (14, 26–30), this validated, quantitative marker for long-term cardiovascular disease complications is readily applicable to clinical management and could be a useful marker of the effect of VSP inhibitors on endothelial cell function. Before BP measurement can be applied as a biomarker in cancer therapy, these findings will need to be reproduced in other clinical settings and described for other agents in this class. It will also be important to determine the sources of pharmacodynamic variability, and the association of this variability to the antitumor effects of these agents.
In the interim, physicians should be aware that large increases in BP can occur in a short period of time with treatment initiation. Attentive measurement and management of these unpredictable elevations in BP could avoid acute complications of hypertension that can occur with less frequent surveillance. As recently noted(31), clinicians should recognize that previously collected databases, typically with fields only for hypertension grading scales or intermittently collected non-standardized office measurements, entail a high degree of variability, making most reports about the relationship between BP and VSP inhibition inconclusive at this time. To draw conclusions on: risk of hypertension among specific patient subsets, effective selection of antihypertensive therapy, or hypertension and cancer therapy outcomes, would be premature and possibly harmful in the long term. (32–36). We advocate careful, prospective patient-oriented studies as the most efficient means by which the complexity of these relationships can be unraveled and applied to improve patient care with this important new class of anticancer agents.
The authors thank Jacqueline Imperial, R.N., Wei Zhang, Ph.D. and Sanja Karovic, for technical assistance in patient care, data analysis, and data management, respectively, and Drs. George Bakris, Luisa Veronese, Keith Flaherty, Peter O'Dwyer, and Chetan Lathia for helpful discussions.
Research Support MLM was supported by a CALGB Foundation Oncology Fellow Clinical Research Award (2005), an ASCO Young Investigator Award (2006), National Institute of General Medical Sciences 5T32GM007019-31 Training in Clinical Therapeutics (2006), and National Cancer Institute K23CA124802 Mentored Career Development Award. This research was also supported by National Center for Research Resources M01-RR000055 administered by the University of Chicago General Clinical Research Center, and a Protocol-specific grant from the University of Chicago Cancer Research Center P30-CA014599. Bayer, Inc. provided sorafenib and measurement of sorafenib plasma concentrations.
Statement of Translational Relevance This study of blood pressure changes in patients who received the vascular endothelial signaling pathway inhibitor sorafenib has two main applications to the future practice of clinical medicine. First, using this accurate measurement method, it is clear that patients differ in the extent to which their blood vessels respond to this drug and this could be important to keeping patients safe from side effects and provide new insights as to how these drugs work. These insights will allow physicians and scientists to learn how to improve the delivery of these drugs and to develop new, more effective drugs. Second, since this effect can be detected very early in the course of treatment, one day physicians might be able to determine whether a patient is getting too little or too much drug by measuring the blood pressure and adjust the patient's dose accordingly, and this could possibly lead to better treatment outcomes.