This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blaney, S. M. Articles by Balis, F. M. Search for Related Content PubMed PubMed Citation Articles by Blaney, S. M. Articles by Balis, F. M. Social Bookmarking                            What's this?

Phase I Clinical Trial of Intrathecal Topotecan in Patients With Neoplastic Meningitis

From the Texas Children’s Cancer Center/Baylor College of Medicine; and M.D. Anderson Cancer Center, Houston, TX; St. Jude Children’s Research Hospital, Memphis, TN; Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Children’s Hospital and Medical Center, Seattle, WA; Children’s Hospital National Medical Center, Washington, DC; and the University of California, San Francisco, San Francisco, CA.

Address reprint requests to Susan M. Blaney, MD, Texas Children’s Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; email: sblaney{at}txccc.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: A phase I trial of intrathecal (IT) topotecan was performed to determine the optimal dose, the dose-limiting toxic effects, and the incidence and severity of other toxic effects in patients 3 years and older with neoplastic meningitis.

Patients and Methods: Twenty-three assessable patients received IT topotecan administered by means of either lumbar puncture or an indwelling ventricular access device (Ommaya reservoir). Intrapatient dose escalation from 0.025 mg to 0.2 mg was performed in the first cohort of patients. Subsequent cohorts of patients were treated at fixed dose levels of 0.2 mg, 0.4 mg, or 0.7 mg. Serial samples of CSF for pharmacokinetic studies were obtained in a subset of patients with Ommaya reservoirs.

Results: Arachnoiditis, characterized by fever, nausea, vomiting, headache, and back pain, was the dose-limiting toxic effect in two of four patients enrolled at the 0.7 mg dose level. The maximum-tolerated dose (MTD) was 0.4 mg. Six of the 23 assessable patients had evidence of benefit manifested as prolonged disease stabilization or response.

Conclusion: The MTD and recommended phase II dose of IT topotecan in patients who are 3 years or older is 0.4 mg. A phase II trial of IT topotecan in children with neoplastic meningitis is in progress.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
INTRATHECAL ADMINISTRATION of anticancer drugs has been an effective strategy for the primary treatment and prevention of leptomeningeal leukemias and lymphomas, but it has not been effective in patients with neoplastic meningitis or in patients with refractory meningeal leukemias. These limitations result in part from the limited number of agents available for intrathecal (IT) administration. Therefore, it is essential to develop new IT agents with novel mechanisms of action.

Topotecan is a topoisomerase I poison that has anticancer activity against a variety of adult and childhood solid tumors. Studies to evaluate the CSF pharmacokinetics of topotecan following systemic administration in a nonhuman primate model demonstrated that the CSF penetration of the active lactone form of topotecan was approximately 30%.^1,2 These findings were subsequently confirmed in children with brain tumors who were receiving continuous infusion topotecan.³ As a result of the excellent CSF penetration, the lack of neurotoxicity after systemic administration, and its novel mechanism of action, studies were performed to evaluate the feasibility of IT topotecan in a nonhuman primate model. These preclinical studies demonstrated that a 0.1 mg intraventricular dose (equivalent to 1.0 mg in humans) was well tolerated. Furthermore, following direct intraventricular topotecan administration, a 450-fold greater CSF exposure could be achieved with 1/100^th of the systemic dose.¹ The results of these preclinical studies served as the basis for the initiation of a phase I study of IT topotecan in patients with neoplastic meningitis.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Eligibility
Patients were eligible for this trial if they were 3 years of age or older and were diagnosed with leukemia, lymphoma, or other solid tumors and overt meningeal tumor involvement that was refractory to conventional therapy. Patients with leukemia/lymphoma were required to have a CSF WBC count 5/µL and evidence of blasts on cytospin preparation or by cytology. Patients with solid tumors had a positive CSF cytology examination or unequivocal evidence of leptomeningeal disease on computed tomography (CT) or magnetic resonance imaging (MRI) scans. Other eligibility criteria included (1) an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; (2) a life expectancy of > 8 weeks; (3) adequate liver function (serum bilirubin < 2.0 mg/100 mL and ALT < three times the upper limit of normal); (4) adequate renal function (serum creatinine < 1.5 mg/100 mL); (5) normal metabolic parameters (serum electrolytes, calcium, and phosphorus); (6) recovery from the toxic effects of prior therapy; and (7) no prior IT therapy within 1 week of starting treatment on this study. Patients could not receive other therapy targeted specifically at their leptomeningeal disease but could receive concomitant chemotherapy to control systemic disease or bulk CNS disease provided that the systemic chemotherapy was not an investigational agent or an agent with significant penetration into the CNS (eg, high-dose methotrexate, thiotepa, high-dose cytarabine, fluorouracil, intravenous mercaptopurine). Study exclusion criteria included clinical evidence of obstructive hydrocephalus or compartmentalization of CSF flow, as documented by a radioisotope CSF flow study, and women of childbearing age who were pregnant or lactating.

Informed consent was obtained from the patient or his/her parent in accordance with individual institutional policies before entry on this study.

Dosage and Drug Administration
Topotecan (hydrochloride salt, adjusted to a pH 3 to 4) was supplied by the Cancer Therapy Evaluation Program, National Cancer Institute (NCI; Bethesda, MD) as a lyophilized formulation in 4-mg vials. The appropriate dose of reconstituted drug was further diluted with preservative-free, pyrogen-free saline to yield a final volume of 5 mL for all doses 0.2 mg and a final volume of 10 mL for all doses > 0.2 mg. Drug was administered at a rate of 2.0 mL/min (total 5 minutes) through a ventricular access device or by means of lumbar puncture. Drug administration was isovolumetric, that is, an amount of CSF equivalent to the volume of drug to be administered was removed before drug administration. In patients with ventricular access devices, the reservoir was flushed slowly for 1 to 2 minutes after drug administration with approximately 2 mL of CSF or normal saline. The reservoir was then pumped four to six times. Patients who received drug by means of a lumbar puncture remained prone, flat, or in the Trendelenburg position for 1 hour after drug administration. All patients were hospitalized overnight after their first dose of topotecan. Patients were observed for a minimum of 2 hours following subsequent doses.

During induction, patients received IT topotecan twice weekly (every 3 to 4 days) for 4 weeks (eight doses). Patients who achieved a complete response (CR) then received four doses of weekly IT topotecan (consolidation), followed by twice-monthly maintenance therapy for 4 months, and then monthly therapy thereafter for up to 8 additional months (continuation therapy). Patients with a partial response (PR) or stable disease (SD) after the initial 4 weeks of induction received 2 additional weeks of twice-weekly induction therapy before proceeding with consolidation and maintenance. Patients with disease progression at the end of induction or at any time during consolidation or maintenance were removed from the study.

Intrapatient dose escalations occurred in the first three patients treated. The first patient enrolled in this study received 0.025 mg IT topotecan twice weekly during the first week of treatment. In the absence of toxicity, this dose was doubled each subsequent week (0.05 mg, 0.1 mg, and 0.2 mg) for the remaining 3 weeks of induction. The second patient received an initial dose of 0.1 mg during the first 2 weeks of therapy; this dose was increased to 0.2 mg thereafter. The third patient commenced treatment at a dose of 0.2 mg and was observed for 4 weeks before entry of additional patients. Subsequent patient cohorts did not undergo intrapatient dose escalation and were enrolled at dose levels of 0.2 mg, 0.4 mg, or 0.7 mg.

A minimum of three patients were entered at each dose level, starting at the 0.2 mg dose level, and the dose level was expanded to six patients if one patient experienced dose-limiting toxicity (grade 3 or greater). When dose-limiting toxicity (grade 3 or greater) was observed in two patients of a cohort of three to six patients receiving the same dose of drug, the maximum-tolerated dose (MTD) was exceeded and an additional three to six patients were added at the dose level immediately below the dose level at which the unacceptable level of toxicity was observed. The dose was not escalated to a higher dose level until at least three patients treated at the previous dose level had received a minimum of at least 4 weeks of induction chemotherapy without dose-limiting toxicity.

Pretreatment and Follow-Up Studies
A complete history, a physical examination, including a detailed neurologic examination, and laboratory studies were obtained before treatment and then weekly throughout the course of the study. Pretreatment laboratory evaluation included complete blood counts, electrolytes, calcium, phosphorus, blood urea nitrogen, creatinine, and liver function tests. CSF studies included a cell count, differential, protein, and glucose. Studies were performed from both ventricular and lumbar CSF in patients with Ommaya reservoirs. Cytospins of CSF were performed and reviewed for the presence of blasts in patients with leukemia/lymphoma, and CSF cytology studies were performed in patients with solid tumors. Bone marrow aspirates that were performed within the 2 weeks preceding protocol entry were required to be negative in patients with leukemia/lymphoma and also were examined as clinically indicated in patients with solid tumors. A pretreatment head MRI or CT scan also was obtained. A radionuclide CSF flow study (¹¹¹n-DTPA or ⁹⁹Tc-DTPA) was required for all patients with solid tumors and for patients with leukemia/lymphoma if CSF analysis, myelogram, CT, or MRI studies indicated evidence of CSF blockage.

During therapy, CSF evaluations were performed with each dose of IT topotecan and 24 hours after the initial treatment with topotecan. Patients with ventricular access devices had lumbar and ventricular CSF evaluated following the 4^th week of therapy, before continuation therapy, and every 3 months during maintenance therapy. Radiographic evaluations in patients with solid tumors who had positive CT or MRI scans were performed after 4 weeks of induction therapy, before the start of continuation therapy, and every 3 months during continuation therapy.

Criteria for Assessment of Toxicity and Response
Toxic effects were evaluated according to the NCI common toxicity criteria (Version 1.0).⁴ Patients were removed from the study if they experienced any grade 3 or greater significant neurotoxicity or other organ toxicity that was judged to be drug related. The grading scale for arachnoiditis, a constellation of signs/symptoms, including fever, nausea, vomiting, headache, and back pain, was arbitrarily determined to be the highest grade of any of the individual signs/symptoms. In addition, arachnoiditis requiring treatment with dexamethasone was defined as grade 3 if the symptoms were rapidly reversible and grade 4 if they were not. Patients with grade 3 arachnoiditis were allowed to continue to receive additional doses of IT topotecan at the previous dose level for subsequent doses.

A CR was defined as the complete clearing of all malignant cells from lumbar CSF (and ventricular CSF in patients with Ommaya reservoirs). In addition, in patients with evidence of disease on CT or MRI scan, complete clearing of radiographic disease for a minimum of 4 weeks was required. A PR was defined as a 50% decrease in the absolute number of malignant cells on cytospin from lumbar CSF (and ventricular CSF in patients with Ommaya reservoirs). In addition, if baseline radiographic studies were positive, a greater than 50% improvement on CT or MRI was required. Progressive disease was defined as at least a 50% increase in the number of malignant cells in the ventricular or lumbar CSF, or an increase of greater than 35% in the size of measurable lesions on CT or MRI scans, or the recurrence of malignant cells in the CSF, or new lesions on CT/MRI in a patient who had previously attained a response. SD was defined as failing to fulfill the criteria for either a CR, a PR, or progressive disease.

Pharmacokinetic Studies
Pharmacokinetic studies of topotecan were performed when possible in patients with indwelling ventricular access devices. Ventricular CSF samples (0.5 mL) were obtained before drug administration and 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 5 hours, and 8 hours after intraventricular dosing. In some patients, a lumbar CSF sample was obtained at 2 or 3 hours following the intraventricular dose.

Sample analysis. In solution, topotecan is unstable and undergoes reversible hydrolysis from the active lactone (closed-ring) form to a less-active hydroxy acid (open-ring) form. The equilibrium favors the lactone form under acidic conditions and the open-ring form at physiologic pH. Samples obtained from patients from the NCI were immediately analyzed for both lactone and total drug concentrations of topotecan using a previously described reverse phase high-performance liquid chromatography (HPLC) assay.⁵ CSF samples obtained from patients at the other participating sites were analyzed for total drug concentrations using a previously described assay.⁶

CSF samples were diluted with mobile phase from the HPLC assay to bring the topotecan concentration within the range of the standards. After dilution, a 20 to 100 µL aliquot of diluted CSF from patients treated at the NCI was immediately injected directly onto the HPLC column. These samples were processed within minutes of when they were drawn from the patient. A second aliquot of CSF was acidified with concentrated phosphoric acid to quantitate the total drug (convert the open-ring species to the lactone form). The acidified sample was injected after it had been at room temperature for at least 2 hours. Topotecan was detected using a fluorescence detector at a _ex of 375 nm and a _em of 470 nm (cutoff filter). In this assay, the open-ring metabolite eluted with the solvent front, and the lactone form of topotecan eluted at 4 minutes.

Samples from patients treated at other sites were placed on dry ice immediately after collection and frozen at -70°C until further analysis. At the time of analysis, these samples were brought to room temperature, acidified, and injected onto the HPLC system as outlined earlier. Topotecan (total drug) was detected using a fluorescence detector at a _ex of 380 nm and a _em of 520 nm (cutoff filter).

Pharmacokinetic data analysis. Monoexponential (n = 1) and biexponential (n = 2) equations were fit to the topotecan lactone and total drug concentration-time data with MLAB (Civilized Software, Bethesda, MD),⁷ using the equation

where C is the plasma concentration of topotecan at time t, A_i is the coefficient, and _i is the rate constant.⁷ Akaike’s information criterion⁸ was used to determine which equation best fit the data. The half-life for each phase of elimination was calculated by dividing 0.693 by the rate constant (_i) for that phase. Model-independent methods were used to calculate other pharmacokinetic parameters. The area under the drug concentration-time curve (AUC) was derived by the linear trapezoidal method⁹ and extrapolated to infinity. CSF clearance following intraventricular topotecan was calculated by dividing the dose by the AUC.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Of the 29 patients enrolled on this study, 23 were assessable for toxicity and response. Six patients were not assessable because they did not complete 4 weeks of induction therapy secondary to rapid disease progression. Three of these six patients were in the first cohort in which the initial starting dose was 0.2 mg. Diagnoses for these three patients included rhabdomyosarcoma (n = 2) and germinoma. Histologic diagnoses for the other three patients with rapid progression included glioblastoma multiforme, breast cancer, and neuroblastoma. These patients with early progression, who received a median of two doses of IT topotecan, did not experience any unusual or severe topotecan-related toxicity. Patient characteristics for the assessable patients are listed in Table 1.

Antitumor Activity
One of the three patients with acute lymphoblastic leukemia (ALL) had a CR to induction therapy. The second patient with ALL also had clearing of his CSF blasts but was removed from the study to receive focal radiation therapy treatment for a third cranial nerve palsy. The third patient with ALL had a marked reduction in his CSF cell count but was removed from the study to receive a bone marrow transplant for treatment of a subsequent systemic relapse after 3 months of IT topotecan. Posttransplant, he received twice-monthly IT topotecan on a compassionate basis without recurrence of his meningeal disease.

Three of the patients with underlying primary CNS tumors also experienced benefit. A patient with leptomeningeal medulloblastoma had her CSF cleared of all malignant cells. A small, nodular leptomeningeal-based lesion noted only in retrospect was stable throughout the full 1-year duration of protocol therapy. This patient was off study for greater than 6 months before experiencing subsequent disease progression. A patient with leptomeningeal gliomatosis had SD for almost 2 years (1 year while on therapy and an additional year after completion of therapy). She experienced an intraparenchymal CNS tumor recurrence 1 year after completing IT topotecan. One other patient with glioblastoma multiforme had disease stabilization for 8 months.

Pharmacokinetics
Ventricular CSF samples for pharmacokinetic studies were obtained with indwelling Ommaya reservoirs in a subset of patients after an intraventricular dose. At the MTD (0.4 mg), the mean (± SD) total topotecan concentration in the ventricular CSF at the first sampling time (15 minutes) was 28 ± 11 µmol/L. Topotecan was rapidly eliminated from the CSF, with an average terminal half-life of 157 ± 54 minutes. Although pharmacokinetic data for the lactone form are available only for a limited number of patients, as expected, lactone drug clearance was more rapid than total drug clearance. Paired data from two patients treated at the 0.2 mg dose level revealed that the CSF lactone clearance was 0.93 mL/min versus 0.24 mL/min for total drug. Disappearance of both lactone and total drug was biexponential (Figs 1 and 2). The pharmacokinetic parameters for total drug following an intraventricular topotecan dose are shown in Table 3.

View larger version (15K): [in this window] [in a new window]   Fig 1. Ventricular CSF concentration-time curves of topotecan, total drug, following an intraventricular dose of 0.2, 0.4, or 0.7 mg. (Points, geometric mean for the number of patients indicated at the 0.2 and 0.4 mg dose levels, actual data from one patient at 0.7 mg; lines, curve fit for the data at each dose level; bars, SD).

View larger version (11K): [in this window] [in a new window]   Fig 2. Representative concentration versus time curve of topotecan total drug and lactone in ventricular CSF from a single patient following a 0.2 mg intraventricular dose of topotecan.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Neoplastic meningitis remains a significant diagnostic and treatment challenge for clinical oncologists. Considerable progress has been made over the past several decades in treating and preventing leptomeningeal leukemias and lymphomas. For a variety of reasons, however, the long-term outcome is poor for most patients with leptomeningeal metastases from an underlying solid tumor or recurrent meningeal leukemia/lymphoma. Direct IT instillation of anticancer drugs is a regional approach that circumvents the blood CSF barrier. The number of anticancer agents that can safely be administered by the IT route, however, is limited. Thus, discovery and testing of new agents with novel mechanisms of action are necessary for the development of effective IT regimens.

In this study, we demonstrated the feasibility of administering an IT topoisomerase poison, topotecan, to children and adults with refractory neoplastic meningitis. Chemical arachnoiditis was the dose-limiting toxicity at the 0.7 mg dose level. Arachnoiditis, which was observed after both intralumbar and intra-Ommaya dosing, was self-limited in one patient and readily reversible with decadron treatment in the other two patients who experienced this toxicity. Although 0.7 mg is somewhat lower than the human equivalent dose of 1.0 mg that was tolerated by nonhuman primates in preclinical studies,¹ it is quite possible that further topotecan escalation would have been possible with concomitant dexamethasone treatment. The pharmacokinetic data from this trial, however, demonstrated a significant pharmacokinetic advantage of IT versus systemic dosing of topotecan, even at the lowest dose levels evaluated. Therefore, further IT topotecan dose escalation with steroid therapy was not attempted, and 0.4 mg was defined as the MTD.

As has been demonstrated with other agents following IT administration, the nonhuman primate model is highly predictive of the pharmacokinetic disposition of antineoplastic agents following intraventricular administration. After normalizing the topotecan dose for intraspecies difference in CSF volume, the preclinical and clinical pharmacokinetic parameters for IT topotecan are similar in both monkeys and humans. The mean terminal half-life for total drug in monkeys was 108 ± 42 minutes versus 157 ± 53 minutes in humans. Likewise, peak ventricular CSF levels normalized to a dose of 1.0 mg in humans were 83 ± 18 µmol/L in monkeys versus 70 ± 27 µmol/L in humans. Thus, the exposures achieved after IT administration of topotecan greatly exceed exposures after systemic administration, which are typically in the nanomolar range.^10,11

In conclusion, these studies have demonstrated the feasibility and safety of administering topotecan intrathecally to patients with neoplastic meningitis. A phase II study designed to evaluate the response rate and duration of progression-free survival following treatment with IT topotecan (0.4 mg per dose) in children with neoplastic meningitis has recently been initiated in the Children’s Oncology Group. Additional phase II trials also are warranted in adults with CNS leukemia or lymphoma or leptomeningeal spread of underlying solid tumors with known sensitivity to topotecan.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Blaney S, Cole D, Godwin D, et al: Intrathecal administration of topotecan in nonhuman primates. Cancer Chemother Pharmacol 36:121–124, 1995[Medline]

2. Sung C, Blaney S, Cole D, et al: A pharmacokinetic model of topotecan clearance from plasma and cerebrospinal fluid. Cancer Res 54:5118–5122, 1994[Abstract/Free Full Text]

3. Baker S, Heideman R, Crom W, et al: Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors. Cancer Chemother Pharmacol 37:195–202, 1996[CrossRef][Medline]

4. National Cancer Institute: Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD, Divisions of Cancer Treatment, National Cancer Institute, 1988

5. Blaney S, Cole D, Balis F, et al: Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res 53:725–727, 1993[Abstract/Free Full Text]

6. Beijnen JH, Smith BR, Keijer WJ, et al: High performance liquid chromatographic analysis of the new antitumor drug SK&F 1048640A (NSC 609699) in plasma. J Pharm Biomed Anal 8:789–794, 1990[CrossRef][Medline]

7. Knott G: MLAB: A mathematical modeling tool. Comput Programs Biomed 10:271–280, 1979[CrossRef][Medline]

8. Yamaoka K, Nakagawa T, Uno T: Application of Akaike’s information criterion (AIC) in the evaluation of linear pharmacokinetic equations. J Pharmacokinet Biopharm 6:165–175, 1978[CrossRef][Medline]

9. Gibaldi M, Perrier D: Estimation of areas, in Gibaldi M, Perrier D (eds): Pharmacokinetics (ed 2). New York, NY, Dekker, 1982, pp 445–449

10. Wall JF, Burris HA, Von Hoff DD, et al: A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SK&F 104864) given as an intravenous bolus every 21 days. Anticancer Drugs 3:337–345, 1992[Medline]

11. Growchow LB, Rowinsky EK, Johnson R, et al: Pharmacokinetics and pharmacodynamics of topotecan in patients with advanced cancer. Drug Metab Dispos 20:706–713, 1992.[Abstract]

Submitted April 5, 2002; accepted August 13, 2002.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. D. Groves, M. J. Glantz, M. C. Chamberlain, K. E. Baumgartner, C. A. Conrad, S. Hsu, J. S. Wefel, M. R. Gilbert, S. Ictech, K. U. Hunter, et al. A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies Neuro-oncol, April 1, 2008; 10(2): 208 - 215. [Abstract] [Full Text] [PDF]

				D. C. Gammon, M. S. Bhatt, L. Tran, A. Van Horn, M. Benvenuti, and M. J. Glantz Intrathecal topotecan in adult patients with neoplastic meningitis. Am. J. Health Syst. Pharm., November 1, 2006; 63(21): 2083 - 2086. [Abstract] [Full Text] [PDF]

				S. M. Blaney, F. M. Balis, S. Berg, C. A.S. Arndt, R. Heideman, J. R. Geyer, R. Packer, P. C. Adamson, K. Jaeckle, R. Klenke, et al. Intrathecal Mafosfamide: A Preclinical Pharmacology and Phase I Trial J. Clin. Oncol., March 1, 2005; 23(7): 1555 - 1563. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blaney, S. M. Articles by Balis, F. M. Search for Related Content PubMed PubMed Citation Articles by Blaney, S. M. Articles by Balis, F. M. Social Bookmarking                            What's this?