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Individualized Patient Dosing in Phase I Clinical Trials: The Role of Escalation With Overdose Control in PNU-214936

From the Departments of Medical Oncology and Biostatistics, Fox Chase Cancer Center, Philadelphia, PA

Address reprint requests to André Rogatko, PhD, Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia, PA 19111; e-mail: a_rogatko@fccc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: A patient-specific dose-escalation scheme using a Bayesian model of Escalation with Overdose Control (EWOC) was conducted to establish the maximum tolerated dose (MTD) of PNU-214936 in advanced non–small-cell lung cancer (NSCLC). PNU-214936 is a murine Fab fragment of the monoclonal antibody 5T4 fused to a mutated superantigen staphylococcal enterotoxin A (SEA).

PATIENTS AND METHODS: Seventy-eight patients with NSCLC were treated with an individualized dose of PNU-214936 calculated using EWOC, based on their anti-SEA antibody level, and given as a 3-hour infusion on 4 consecutive days.

RESULTS: Fever (82%; grade 3 to 4, 2.6%) and hypotension (57%; grade 3 to 4, 9%) were the most common toxicities. Eight dose-limiting toxicities occurred, as defined as any grade 4 toxicity occurring within the first 5 days. The MTD was defined as a function of pretreatment anti-SEA antibody level. MTD ranged from 103 ng/kg for patients with anti-SEA concentrations 10 pmol/mL, to 601 ng/kg for patients with anti-SEA concentrations of 91 to 150 pmol/mL. A minor tumor response was demonstrated in five of 66 assessable patients.

CONCLUSION: EWOC determined phase I doses of PNU-214936 that were adjusted for patient anti-SEA antibody level, while safeguarding against overdose. Furthermore, the method permitted the construction of a dosing algorithm that would allow patients in subsequent clinical investigations to be treated with a dose of PNU-214936 that is tailored to their specific tolerance for the agent, as reflected by their pretreatment anti-SEA.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The primary objectives of phase I clinical trials have customarily been to characterize the toxicity profile of a new treatment regimen and to determine the appropriate dosing level for subsequent clinical evaluation of efficacy. While new advances in biologically targeted therapies may obviate the relevance of toxicity in cancer treatment, it is still the primary end point in phase I clinical trials, and a major concern throughout all phases of therapy development. Since it is generally assumed that the activity of a cytotoxic agent increases with dose and that toxicity is a prerequisite for optimal antitumor activity [1], the maximum tolerated dose (MTD) typically corresponds to the highest dose associated with a tolerable level of toxicity. The MTD is defined as the dose expected to produce some degree of medically unacceptable, dose-limiting toxicity (DLT) in a specified proportion of (theta) patients. The phase I target dose (MTD) is, therefore, the same for every member of the patient population, as no allowances are made for individual patients differences in susceptibility to treatment [2]. However, recent improvements in our understanding of drug metabolism have led to the development of anticancer therapies that accommodate intrinsic patient differences in drug tolerance. Analyses of pharmacokinetics and the genetics of drug metabolism have led to the development of new treatment paradigms that accommodate individual patient needs [3-6]. Such methods adjust the dose level according to measurable patient characteristics to obtain an individualized target drug exposure.

This article describes the utilization of a patient-specific dosing scheme in the statistical design of a phase I clinical trial of the superantigen-based immunotherapy PNU-214936 involving patients with advanced non–small-lung cancer (NSCLC). PNU-214936 consists of the murine Fab fragment of the monoclonal antibody 5T4 [7,8] genetically fused to a mutated superantigen (SAg) staphylococcal enterotoxin A (SEA). SAgs bind to major histocompatibility complex (MHC) class II molecules [9-11] and subsequently activate a high number of cytotoxic and helper T lymphocytes by interacting with the constant part of the T cell receptor V_ß (TcR V_ß) chain [12,13]. PNU-214936 localizes the bacterial SAg to tumor sites by the adenocarcinoma specific antibody 5T4, to target activated cytotoxic T lymphocytes [14,15]. PNU-214936 and other similar Fab-SAg fusion proteins have successfully been used to reduce and eliminate metastatic tumor burden in mice with established experimental tumors [16]. This therapeutic effect has been accompanied by a massive infiltration throughout the tumor, of cytotoxic T lymphocytes that actively produce tumoricidal cytokines such as tumor necrosis factor-alpha and interferon-gamma [17]. PNU-214936 has been mutated in position 227 of the SEA moiety by replacing an aspartate with alanine to reduce its affinity toward MHC class II molecules. This mutation results in 100-fold less MHC class II binding as compared to PNU-214565, the predecessor molecule containing wild-type SEA [18]. This mutation was postulated to confine the SEA-induced inflammatory response to tumor sites and limit the toxicity associated with systemic immune activation.

Previous clinical and preclinical studies have demonstrated that the action of PNU-214936 is moderated by the neutralizing capacity of anti-SEA antibodies [19]. Therefore the MTD was dependent on the level of such neutralizing antibodies in each patient. Accordingly, it was necessary to define the MTD as a function of each patient's plasma concentration of anti-SEA antibodies. This consideration required a continual adjustment of the Bayesian model used to tailor the dose to each patient individually. The dose escalation in this phase I trial was designed according to a novel method referred to as Escalation with Overdose Control (EWOC) [20]. This method selects dose levels for use in the trial so that the predicted proportion of patients receiving a dose level above the MTD is no greater than a specified threshold. Prior observations demonstrated toxicity to be inversely correlated with pretreatment plasma anti-SEA Ab levels; therefore, a dosing model incorporating the anti-SEA Ab concentration for dose selection was used. Thus, in this phase I trial, dose levels were specifically tailored to a pretreatment assessment of a patient's susceptibility to the biologic effects of the agent being tested.

	PATIENTS AND METHODS

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Patient Population
Eligibility stipulated histologically or cytologically confirmed NSCLC age older than 18 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. All patients had adequate bone marrow function (WBC 3000/mm³; absolute neutrophil count 1500/mm³; platelets 100,000/mm³; and hemoglobin < 10g/dL), renal function (creatinine < 1.5x the upper limit of normal), and hepatic function (bilirubin < 2x the upper limit of normal; AST/ALT < 3x the upper limit of normal), and had not received chemotherapy, radiotherapy, or immunotherapy within 4 weeks of the start of treatment. Exclusions included exertional hypoxemia or pulse oxymetry less than 89%; uncorrected hypercalcemia; poorly controlled hypertension; ongoing treatment with beta blockers, anticoagulants, or corticosteroids; pregnancy or breast feeding; intercurent malignancy or brain metastasis; active infection; symptomatic cardiac disease or arrhythmia; history of cerebrovascular accident or seizure disorder; autoimmune disease or seropositivity for HIV; previous exposure to murine monoclonal antibody; or positive human antimouse antibody (HAMA) titer. Written informed consent was obtained in accordance with federal, state, and institutional review board guidelines.

Treatment Plan
Each patient was treated with an individual dose based on the pretreatment anti-SEA Ab concentration, and adjusted for body weight. As a safety precaution, the first three patients received a 25-ng/kg dose of PNU-214936 regardless of their anti-SEA titer. The starting dose was chosen based on toxicology studies performed in cynomolgus monkeys to provide a 240-fold safety margin as determined by the no-observed-adverse-effect-level (NOAEL). Anti-SEA Ab concentrations were obtained within 3 weeks of the start of treatment and were used to calculate a patient's individual dose according to a Bayesian dose-escalation program called EWOC [20]. This dose information (in ng/kg, rounded to the nearest whole nanogram) was communicated to the investigator, and the final total dose was calculated based on multiplication of the ng/kg dose by the patient's pretreatment body weight on day 1. This same total dose was administered on days 2, 3, and 4 of the first cycle, unless dose adjustments or delays were required. A second cycle of therapy was allowed for a patient who showed stable disease or tumor regression. Second-cycle dosage was calculated based on the day-28 anti-SEA Ab concentration, with a 25% dose reduction in patients who experienced DLT during their first cycle. Additional cycles of therapy were allowed only for patients who showed a tumor response following the second cycle.

According to the formal definition of DLT, the assessment of each patient's response to treatment required that the patient be followed for up to 28 days after treatment onset. Consequently, patients were occasionally accrued to the trial before the responses of all previously treated patients could be definitively determined. This raised the issue of whether treatment of each newly accrued patient should be delayed until the data from all prior patients was available. Since this problem is common in cancer phase I clinical trials, it is important to note that the method (EWOC) used to design the trial does not require knowing the responses of all previously treated patients before the dose for a new patient can be ascertained. Instead, to reduce the time needed to complete the study, each patient can be treated at the dose determined on the basis of whatever data is currently available. In the present trial, it was left to the discretion of the principal investigator to determine if the treatment of any patient was to be initiated as soon as possible or postponed until resolution of one or more unknown treatment responses.

DLT
DLT was defined as any grade 4 toxicity potentially attributable to study drug, experienced within 24 hours after the last infusion of the first cycle, as previous experience with the predecessor molecule PNU-214565 demonstrated a lack of delayed toxicities and acute toxicities typically resolving within 24 hours [19]. Because of the possibility of cytokine-induced shock and vascular leak syndrome with SAg therapy, grade 2 to 4 cardiovascular toxicity (eg, hypotension requiring fluid replacement) was considered a DLT. Grade 4 hematological toxicity that resolved within 24 hours without clinical consequences was not considered a DLT. Grade 4 hypotension was defined as requiring administration of pressor agents, and grade 4 vascular leak syndrome was defined as requiring pressor support and/or ventilatory support. If DLT occurred for a given patient, the patient was eligible to receive additional treatment at a reduced dose level. If the adverse effect subsided to grade 2 (grade 0 for cardiovascular toxicity) within 48 hours from the start of the prior infusion, the treatment cycle could be continued at a 25% dose reduction. If a repeated episode of DLT occurred at the modified dose level, the patient was withdrawn from all further treatment with PNU-214936.

MTD
The MTD is defined to be the dose of PNU-214936 that, when administered as an intravenous infusion to patients with a particular level of anti-SEA Ab, results in a probability of = 0.10 that DLT occurs. Thus, the MTD is defined as a function of pretreatment anti-SEA Ab, where MTD(a) is the dose expected to induce DLT in 10% of patients with anti-SEA Ab equal to a.

Dose-Toxicity Model
Information about patient differences in susceptibility to treatment was incorporated into the design through a statistical model for the probability of DLT. The model is given by:

where , ß, and are unknown. It was assumed that ß 0 and 0, so that the probability of DLT is an increasing function of dose (for fixed anti-SEA), and, since anti-SEA has a neutralizing effect on PNU, a decreasing function of anti-SEA (for fixed dose). Figure 1 illustrates the functional dependence of the dose-toxicity model on both the PNU dose level and the pretreatment anti-SEA concentration.

View larger version (14K): [in this window] [in a new window]   Fig 1. Model relating the probability of dose-limiting toxicity (DLT) at the minimum permissible PNU dose 25 ng/kg as a function of pretreatment anti–staphylococcal enterotoxin A (SEA) concentration (left portion). Probability of DLT as a function of PNU dose for patients with anti-SEA concentration 1,800 pmol/mL (right portion).

The maximum allowable dose for any patient was the minimum between 50,000 ng/kg and his or her pretreatment anti-SEA Ab concentration (pmol/mL) multiplied by a factor of 50.

Using the Bayesian approach, information available before the onset of the trial was incorporated through a prior probability distribution for the unknown parameters of the dose-toxicity model. To facilitate the elicitation of the prior, the dose-toxicity model was reformulated in terms of parameters the clinicians could readily interpret. Since estimation of the MTD was the primary statistical aim of the trial, and the clinicians could easily understand the probability of DLT associated with selected combinations of dose and anti-SEA, the model was re-expressed in terms of:

and

We note that ₁ and ₂ are the probabilities of DLT when the minimum allowable dose 25 ng/kg is administered to patients with pretreatment anti-SEA c₁ = 0.05 and, c₂ = 1,800, respectively, where c₁ and c₂ were chosen to span the range of anti-SEA concentrations expected in the trial, and _max is the MTD associated with the maximum anticipated concentration of anti-SEA. Based on these parameters, prior information was expressed in terms of a prior probability density function H for = [_max, ₁, ₂]. Since the probability of DLT at a given dose is a decreasing function of anti-SEA, we have ₁ < ₂. Furthermore, since the MTD was assumed to be greater than 25 ng/kg for all values of anti-SEA, we have ₁ < , where = 0.1 is the target probability of DLT at the MTD. Consequently, the parameter space associated with (₁, ₂) was taken to be = {(x,y): 0 x 0.1, 0 y x}. The prior distribution of was then specified by assuming _max and (₁, ₂) to be independent a priori, with ₁ and ₂ jointly distributed as a uniform on and with 1n(_max) distributed as a uniform on [1n (25), 1n(50,000)].

Dose escalation was based on the marginal posterior distribution function of the MTD for patients with pretreatment anti-SEA Ab concentration equal to a pmol/mL. This function, denoted _a, was constructed using the data D_k available at the time that the dose for the k-th patient is determined. Specifically:

That is, _a (X|D_k) was an estimate, based on the data D_k that patients with anti-SEA Ab equal to a have an MTD no greater than X. The dose (ng/kg) for each patient was determined so that, on the basis of all available data, the probability of DLT was 0.10, and the probability that the dose exceeded the MTD was 0.25. Thus, if the k-th patient has anti-SEA Ab equalinga, then he or she would receive the dose x_k(a) such that _a(x_k(a)  D_k) = 0.25.

At the time of each dose assignment, the method made use of all data available from the parallel trials of PNU-214936 in advanced NSCLC being conducted in the United States and Europe.

	RESULTS

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Patient Demographics and Other Baseline Characteristics
Seventy-eight patients were enrolled onto the study and were treated with PNU-214936 between August 10, 1998, and November 22, 2000, at three sites in the United States (40 patients) and three sites in Europe (38 patients). Forty-five male patients and 33 female patients were treated. Patient ages ranged from 29 to 79 years, with a mean age of 56.5 years. Thirty-three patients had a baseline ECOG performance status of 0, and 45 patients had a performance status of 1. Seventy-four patients were white, three patients were black, and one patient was Malaysian. Fifty-three patients had adenocarcinoma, seven patients had squamous cell carcinoma, and 18 patients had other or not otherwise specified histology. Fifty-one patients had received chemotherapy, 22 patients had undergone prior surgery, and 33 patients had received radiotherapy either with or without chemotherapy.

Treatment With PNU-214936
All patients were treated with PNU-214936 according to each individual patient's baseline anti-SEA antibody level. Overall, the 78 patients received 106 cycles of therapy, with all 78 patients completing the study protocol. Each cycle consisted of a 3-hour infusion of PNU-214936 given daily for 4 days. Fifty-one patients received one cycle of therapy, 26 patients received two cycles of therapy, and one patient received three cycles of therapy.

Dosage Assignment
Doses assigned were based on the patient's baseline anti-SEA Ab level. These led to the large range of daily dosage, ranging from 1,872 to 142,786 ng/kg. The cumulative dose range per cycle was 7,490 to 571,144 ng/kg, with total cumulative dosages per patient of 7,490 ng/kg to 952,037 ng/kg. Figure 2 demonstrates the continuous adjustment of patient doses by EWOC as a function of their anti-SEA level as toxicity information becomes better defined over the course of this trial. The amount of information gained during the trial was evidenced by the magnitude of change in the recommended dose levels. For example, the recommended PNU dose for patients with anti-SEA value of 100 pmol/mL changed from 11 ng/kg at trial onset to 601 ng/kg by trial termination. The latter (uppermost) curve corresponds to the dose level recommended for phase II evaluation. The dose level recommended for phase II evaluation, 90% highest posterior density credible interval for the MTD and permissible range of dose levels (ie, minimum and maximum allowable doses) as a function of pretreatment anti-SEA are shown in Table 1. Figure 3 displays the marginal posterior distribution of the MTD for three selected pretreatment anti-SEA concentrations. It can be seen that the uncertainty around the recommended dose for lower anti-SEA values is smaller (narrower peak) than for higher ones, since more patients with low anti-SEA values were seen in our sample than with higher ones (as it can be seen in Figure 4).

View larger version (14K): [in this window] [in a new window]   Fig 2. Recommended dose (ng/kg) as a function of pretreatment anti–staphylococcal enterotoxin A (SEA) concentration (pmol/mL) at the beginning (dotted line) and end of the trial (solid line).

View larger version (21K): [in this window] [in a new window]   Fig 3. Marginal posterior distribution of the maximum tolerated dose (ng/kg) for three selected pretreatment anti–staphylococcal enterotoxin A (SEA; pmol/mL) concentrations. recom., recommended.

View larger version (16K): [in this window] [in a new window]   Fig 4. Dose (ng/kg) by baseline anti–staphylococcal enterotoxin A (SEA) antibody concentration (pmol/mL) for patients with dose-limiting toxicity (squares) and without (points).

MTD
The MTD is defined as a function of pretreatment anti-SEA Ab: MTD(a) is the dose expected to induce DLT in 10% of patients with anti-SEA Ab equal to a. A total of 78 patients were treated, with the occurrence of DLT in eight patients (three US, five Europe). Figure 1 shows the MTD as a function of pretreatment anti-SEA Ab.

Tumor Response
Efficacy evaluations determined by objective tumor response based on tumor measurements and/or assessable disease were available for 66 patients. Twelve patients were non assessable. Forty-one patients demonstrated progressive disease by day 28 of cycle 1. Twenty-five patients had stable disease at day 28 of cycle 1. A minor response of greater than 25% tumor regression was demonstrated in eight (12%) of 66 assessable patients. Five of those eight patients had minor response (MR) persisting 4 weeks or longer. The maximal tumor regression was 49%.

	DISCUSSION

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Phase I clinical trials have conventionally used cohorts of 3 or 6 patients with doses escalated chronologically, typically according to a modified Fibonacci sequence in order to assess toxicity and define MTD. This methodology generally leads to the majority of patients undergoing treatment at subtherapeutic doses as well as an imprecise estimate of the MTD. The incorporation of covariates into the traditional design is accomplished by conducting separate trials and estimating separate MTDs for a limited number of patients subgroups defined in terms of the covariate. This piecewise approach does not permit a refined adjustment of dose according to the covariate, provides no definite guidelines for constructing the patient subgroups and, since there is no explicit functional relationship assumed between the MTD and covariate, provides only ad hoc methods for using all available information by linking the data from the separate trials. This historical definition of MTD quantifies the average response of a patient population to a particular treatment, but does not allow for individual differences in susceptibility to the treatment [3]. Recent developments in understanding the genetics of drug-metabolizing enzymes shed light on the importance of individual patient differences in pharmacokinetic as well as other relevant clinical parameters [3-6]. The observation that impaired renal function can result in reduced clearance of carboplatin led to the development of dosing formulas based on renal function that permit careful control over individual patient exposure [21]. Another example is accounting for the contribution of prior therapy by establishing separate phase II doses for heavily pretreated and minimally pretreated patients.

To address these concerns, methods have been developed which permit the incorporation of patient-specific characteristics into the statistical design of phase I clinical trials. For example, the Quantitative Assessment design of Mick and Ratain [22] used a least squares fit to a pharmacodynamic model to adjust phase I doses according patient WBC count nadir. O'Quigley et al [23] described the application of the Continual Reassessment method applicable to the case where separate MTDs are determined for patients with and without prior treatment. Piantadosi and Liu [24] developed a Bayesian dose escalation scheme based on covariate information that could only be acquired from each patient after treatment onset. According to this design, covariate information was used to improve the efficiency with which the MTD was determined and but did not provide a foundation for a tailored dosing regimen. Among these methods, EWOC is unique in that it permits refined adjustment of dose according to a pretreatment assessment of covariate and directly incorporates patient safety into the dosing algorithm. Babb et al [20] conducted a simulation study to compare the performance of EWOC with four Fibonacci-based phase I trial designs [25]. These simulations showed EWOC to be effective in controlling the frequency of overdosing in a phase I trial. EWOC assigned fewer patients to either subtherapeutic or severely toxic dose levels, treated more patients at optimal dose levels, and estimated the MTD with smaller average bias and mean squared error.

EWOC is the first Bayesian statistical design method applied to a cancer phase I clinical trial that not only guides the dose escalation from patient to patient, but also permits a personalization of the dose level to each specific patient. This article provides a detailed account of the application of EWOC with covariate adjustment whereby the aim is to escalate as quickly as possible toward MTD while safeguarding against overdosing. We describe the utilization of covariate information in a phase I study of PNU-214936 involving patients with advanced NSCLC. Previous clinical and preclinical studies demonstrated that the action of PNU is moderated by the neutralizing capacity of anti-SEA antibodies. Based on this, the MTD was defined as a function of, and dose levels were adjusted according to, each patient's plasma concentration of anti-SEA antibodies. Thus, we describe a phase I trial wherein dose levels were specifically tailored to a pretreatment assessment of patient susceptibility to treatment. In this PNU-214936 trial of a mutated superantigen fused to monoclonal antibody 5T4, we used EWOC to individually select the dose for each patient based on his/her anti-SEA level as well as previous patient toxicity data. We set the probability of DLT or = 0.1, and the probability of exceeding MTD or at 0.25. Conventional Fibonacci phase I trial designs use a = 1/3, and do not allow for adjustments. The value selected for determines the rate of change in dose level between successive dose determinations. Low values result in a cautious escalation scheme with relatively small increments in dose, while high values result in a more aggressive escalation. In the PNU trial, was initially set at 0.25 and then allowed to increase to 0.5 in a predetermined stepwise manner in the absence of unacceptable toxicity. At the initiation of this trial, there was greater uncertainty about the MTD, and a small value of afforded protection against the possibility of administering dose levels much greater than the MTD. As the trial progressed, uncertainty about the MTD declined and the likelihood of selecting a dose level significantly above the MTD became significantly smaller. Consequently, a relatively high probability of exceeding the MTD could be tolerated near the conclusion of the trial because the magnitude by which any dose exceeded the MTD is expected to be small.

The total number of patients treated during the phase I trial is far in excess of the number of patients typically treated in a phase I trial. This was a consequence of the need to accurately assess the functional role of the covariate in the dose-toxicity relationship and is a reflection of a general need for larger samples whenever patient specific dosing is attempted in a phase I trial. However patient specific dosing allows for greater precision in determining the phase II dose, as EWOC allows one to rapidly attain potentially therapeutic doses, while minimizing the risk for DLT. This design may therefore allow one to have a more accurate preliminary gauge of the potential efficacy of a novel agent.

Accrual to the trial was not stratified according to patient anti-SEA levels. As a result, relatively few patients with high anti-SEA concentrations were treated with PNU, yielding relatively imprecise estimates of the recommended doses for these patients. However, the data (highest posterior density credible intervals for the MTD) indicated that with 95% confidence the recommended dose for patients with high anti-SEA exceeds the amount of agent that is clinically practical. Consequently, PNU-214936 was not recommended for patients with high anti-SEA values in subsequent investigations.

This article describes the first trial to evaluate PNU-214936 in non–small-cell lung cancer. The primary objective was to define the MTD of PNU-214936 as a function of pretreatment anti-SEA Ab antibody levels. The EWOC design allowed the definition of the MTD based on baseline plasma anti-SEA Ab levels. As a result, the trial permitted the construction of a dosing algorithm (Table 1) that would allow patients in subsequent clinical investigations to be treated with a dose of PNU-214936 that is tailored to their specific tolerance for the agent as reflected by their pretreatment anti-SEA. We have demonstrated the feasibility of individualizing patient dosing based on pretreatment covariate information. This methodology can be adapted to other investigational agents to more accurately and rapidly arrive at therapeutic doses in phase I clinical trials.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have 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. Acted as a consultant within the last 2 years: Joan Schiller, University of Wisconsin.

	Acknowledgment

 
We are grateful for the helpful insight and suggestions provided by the reviewers.

	NOTES

 
Supported by grants CA06927 and CA-92769 from the National Cancer Institute, a Tobacco Formula Grant from the State of Pennsylvania, and an appropriation from the Commonwealth of Pennsylvania.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted December 6, 2002; accepted September 26, 2003.

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