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Randomized, Placebo-Controlled Phase II Study of Vandetanib Plus Docetaxel in Previously Treated Non–Small-Cell Lung Cancer

John V. Heymach, Bruce E. Johnson, Diane Prager, Edit Csada, Jaromír Roubec, Milo Peek, Irena pásová, Chandra P. Belani, István Bodrogi, Shirish Gadgeel, Sarah J. Kennedy, Jeannie Hou, Roy S. Herbst

From the Dana-Farber Cancer Institute, Boston, MA; UCLA Medical Center, Los Angeles, CA; University of Szeged, Szeged; National Institute of Oncology, Budapest, Hungary; University Hospital Ostrava-Poruba, Ostrava; University Hospital, Medical Faculty in Pilsen, Charles University, Prague, Czech Republic; Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA; Wayne State University/Karmanos Cancer Institute, Detroit, MI; AstraZeneca, Alderley Park, Macclesfield, United Kingdom; AstraZeneca, Wilmington, DE; and The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Roy S. Herbst, MD, PhD, Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX 77030-4009; e-mail: rherbst{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor-2 and epidermal growth factor receptor kinase activity. The activity of vandetanib plus docetaxel was assessed in patients with previously treated non–small-cell lung cancer (NSCLC).

Patients and Methods This two-part study comprised an open-label run-in phase and a double-blind randomized phase. Eligible patients had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of first-line platinum-based chemotherapy. The primary objective of the randomized phase was to prolong progression-free survival (PFS) in patients receiving vandetanib (100 or 300 mg/d) plus docetaxel (75 mg/m² intravenous infusion every 21 days) versus placebo plus docetaxel. The study was designed to have more than 75% power to detect 50% prolongation at a one-sided significance level of P < .20. Secondary objectives included objective response rate, overall survival, safety and tolerability.

Results In the randomized phase (n = 127), median PFS was 18.7 weeks for vandetanib 100 mg plus docetaxel (n = 42; hazard ratio v docetaxel = 0.64; one-sided P = .037); 17.0 weeks for vandetanib 300 mg plus docetaxel (n = 44; hazard ratio v docetaxel = 0.83; one-sided P = .231); and 12 weeks for docetaxel (n = 41). There was no statistically significant difference in overall survival among the three treatment arms. Common adverse events included diarrhea, rash, and asymptomatic prolongation of corrected QT (QT_C) interval.

Conclusion The primary objective was achieved, with vandetanib 100 mg plus docetaxel demonstrating a significant prolongation of PFS compared with docetaxel in relation to the prespecified significance level. On the basis of these encouraging data, phase III evaluation of vandetanib 100 mg plus docetaxel in second-line NSCLC has been initiated.

	INTRODUCTION

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Patients with non–small-cell lung cancer (NSCLC) have a 5-year survival rate of only 15%,¹ and more effective treatment options are clearly needed.¹ Validated therapeutic targets in NSCLC include vascular endothelial growth factor (VEGF), a key mediator of tumor angiogenesis, and epidermal growth factor receptor (EGFR).^2-5 EGFR is known to regulate the production of VEGF and other proangiogenic factors,⁶ and resistance to EGFR inhibition has been associated with increased VEGF plasma levels,⁷ suggesting that combined inhibition of the VEGF/VEGF receptor (VEGFR) and EGFR pathways may be more effective than inhibiting either pathway alone. This hypothesis is supported by the encouraging antitumor activity observed in a phase I/II study of bevacizumab plus erlotinib in recurrent NSCLC (response rate, 20.0%; median survival, 12.6 months).⁸

Vandetanib (ZACTIMA; ZD6474; AstraZeneca, Macclesfield, UK) is a once-daily, oral anticancer drug that inhibits VEGFR- and EGFR-dependent signaling.⁹ It is also a potent inhibitor of RET (Rearranged during Transfection) receptor tyrosine kinase activity, which is frequently activated by mutation or rearrangement in thyroid cancer.^10-12 Phase I evaluation in American/Australian¹³ and Japanese¹⁴ patients with advanced tumors showed that vandetanib was generally well tolerated at daily oral doses of 300 mg/d or lower; notably, four of nine Japanese patients with refractory NSCLC experienced objective tumor responses ranging from 90 to 438 days.¹⁴

We report the results of a two-part, multicenter phase II study (6474IL/0006) of vandetanib with docetaxel in patients with locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of platinum-based chemotherapy. The study consisted of an open-label run-in phase and a double-blind placebo-controlled randomized phase. A broad population was recruited, including patients with squamous cell histology and brain metastases.

	PATIENTS AND METHODS

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Patients
The main eligibility criteria were histologic or cytological confirmation of locally advanced or metastatic stage IIIB/IV NSCLC after failure of first-line platinum-based therapy, age at least 18 years, a WHO performance status of 0 or 1, a life expectancy of at least 12 weeks, and normal end organ function. Patients with squamous cell histology were eligible, and brain metastases were permitted if treated at least 4 weeks before study entry and clinically stable without steroid treatment for 1 week. Exclusion criteria included previous treatment with docetaxel or EGFR/VEGFR signaling inhibitors; chemotherapy within the last 4 to 6 weeks; or radiation therapy within the last 4 weeks. The trial was approved by all relevant institutional ethical committees, and conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and the AstraZeneca Bioethics policy. Each patient provided written informed consent.

Study Design and Treatment
Both study parts consisted of continuous 21-day treatment periods in which patients received once-daily oral vandetanib (100 or 300 mg) and docetaxel (75 mg/m² intravenous infusion over 1 hour on day 1 of each 21-day cycle; Fig 1). Patients continued treatment until progressive disease, unacceptable toxicity, or withdrawal of consent.

View larger version (24K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study design. NSCLC, non–small-cell lung cancer.

PKs
Plasma–concentration time profiles of vandetanib and docetaxel were determined in the run-in phase (see Figs A1 and A2 for details regarding sample collections and analysis).

Statistical Considerations
The primary objective of the randomized phase was to investigate whether vandetanib (100 or 300 mg) plus docetaxel prolonged PFS compared with placebo plus docetaxel. Secondary assessments included objective response rate, overall survival, safety and tolerability. All patients were included in the efficacy and safety analyses. PFS was determined from objective tumor assessments performed at screening and every 3 weeks for the first 12 weeks, then every 6 weeks until progression or withdrawal of consent. Tumor responses were assessed and categorized using Response Evaluation Criteria in Solid Tumors (RECIST).¹⁵ The randomized phase was designed to have more than 75% power to detect a 50% prolongation of PFS at a one-sided significance level of P < .20. Because the trial was designed to assess whether vandetanib showed sufficient promise to warrant further investigation, a significance level of .20 (rather than .05) was used, and no adjustment was made for multiple comparisons (100 mg vandetanib v placebo; 300 mg vandetanib v placebo). Statistical results are presented with one-sided P values in accordance with the study design, and, additionally, with the corresponding two-sided P values for completeness. Analysis of PFS was planned after approximately 90 progression events; to achieve this, it was considered necessary to recruit 120 patients (40 per arm) to the randomized phase. Overall survival was determined at a minimum of 18 months after the last patient had entered the study. Patients who continued to receive study treatment beyond the time of PFS analysis remained blinded. If patients discontinued study treatment because of toxicity, but before disease progression, they continued to be followed for disease progression. Patients who had not progressed at the time of analysis were censored at the time of their most recent RECIST evaluation. PFS and overall survival were analyzed on an intention-to-treat basis using a Cox proportional hazards regression model that allowed for the effect of treatment and included terms for tumor stage and number of organs involved. Patients who had not experienced disease progression or died at the time of analysis were censored at the time of their last objective tumor assessment. Exploratory analyses of PFS and overall survival were performed separately for subgroups defined by histology (adenocarcinoma or nonadenocarcinoma) and by sex (male or female), using the same approach as for the primary analysis (ie, Cox proportional hazards regression model).

Safety and Tolerability
Adverse events recorded at each scheduled visit were coded (MedDRA version 7.1) and assessed using the National Cancer Institute Common Toxicity Criteria (CTC) version 2. Unless additional ECGs were clinically indicated, 12-lead ECGs were performed during screening, pretreatment (day 1); days 1, 8, and 15 of treatment periods 1 and 2; day 1 of subsequent periods; and at the end of the study. Prolongation of the corrected QT (QT_C) interval was evaluated centrally and defined as a single measurement of at least 550 ms, or that showed an increase of at least 100 ms from baseline; or two consecutive measurements (within 48 hours of each other) of at least 500 ms but less than 550 ms, or that showed an increase of at least 60 ms from baseline to at least 460 ms.

	RESULTS

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Run-In Phase
Patients recruited to the run-in phase received vandetanib 100 mg plus docetaxel (V100+doc; n = 4) or vandetanib 300 mg plus docetaxel (V300+doc; n = 11); two additional patients enrolled onto study did not receive vandetanib during the run-in phase because of docetaxel-related toxicity on day 1. Both regimens were tolerated with a manageable adverse event profile (Table A1, online only). Combined use did not cause detectable changes in PK exposure to either drug (Figs A1 and A2, online only). These results supported continuation to the randomized phase of the study.

Randomized Phase
Between May 2003 and July 2004, 127 patients from 27 centers in the United States, the Czech Republic, and Hungary entered onto the randomized phase of the study. Patient characteristics and baseline demographics were generally similar in the three arms (Table 1), although there was a slightly higher number of females in the V100+doc arm and stage IV patients in the V300+doc arm. Among all patients, the majority were current or previous smokers (88%), 50% presented with histology other than adenocarcinoma (including 29% squamous), and approximately 10% had treated brain metastases. Patient disposition at the time of data cutoff for analysis of PFS is summarized in Table A2 (online only).

View larger version (22K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Kaplan-Meier plot for progression-free survival in the randomly assigned intention-to-treat population. (B) Kaplan-Meier plot for overall survival in the randomly assigned intention-to-treat population.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Exploratory analysis of progression-free survival (PFS) in the randomly assigned intention-to-treat population for (A) adenocarcinoma versus other histologies and (B) males versus females. HR, hazard ratio.

Overall survival was analyzed at 93 deaths (73%; data cutoff, March 15, 2006) and showed no statistically significant difference between either combination arm compared with docetaxel alone (Fig 2B; Table 2). The estimated hazard ratios for the V100+doc and V300+doc arms compared with docetaxel alone were 0.91 (P = .361 [one-sided] and .723 [two-sided]; 95% CI, 0.55 to 1.52) and 1.28 (P = .833 [one-sided] and .334 [two-sided]; 95% CI, 0.78 to 2.10), respectively. Median overall survival was 13.4 (docetaxel alone), 13.1 (V100+doc), and 7.9 (V300+doc) months.

Safety and Tolerability
Overall, the most common adverse events were diarrhea, fatigue, neutropenia and nausea (Table 3). Among adverse events typically associated with inhibitors of VEGFR or EGFR signaling, diarrhea and rash were most frequent and severe in patients receiving V300+doc (Table 3). Nevertheless, across all three treatment arms, adverse events were generally manageable using standard approaches. Adverse events considered by the investigator to be vandetanib related led to the discontinuation of vandetanib 300 mg in seven patients (n = 6, skin/subcutaneous disorders; n = 1, diarrhea) and vandetanib 100 mg in one patient (toxic skin eruption). In some cases, skin toxicity was observed in sun-exposed areas, consistent with a photosensitivity reaction. Nine patients discontinued docetaxel because of docetaxel-related adverse events (n = 3, docetaxel alone; n = 2, V100+doc; n = 4, V300+doc); the most common adverse event in this category was neutropenia (n = 3, including two patients with febrile neutropenia).

No clinically symptomatic changes in ECG were observed between treatment groups, and all episodes of QT_C prolongation were asymptomatic and manageable with dose interruption and/or reduction. One patient in the run-in phase experienced asymptomatic, nonsustained ventricular tachycardia in the setting of electrolyte abnormality and QT_C prolongation, both of which normalized with electrolyte repletion. The incidence of protocol-defined QT_C prolongation was numerically higher in the V300+doc arm (n = 5) compared with the V100+doc arm (n = 2); no patient in the docetaxel-alone arm experienced QT_C prolongation. The median change in QT_C interval from baseline at 6 weeks was +2 ms (docetaxel alone; n = 21), +14 ms (V100+doc; n = 29), and +26 ms (V300+doc; n = 25).

The majority of all deaths (78%) resulted from disease progression (ie, primary cause of death recorded as NSCLC). Six deaths that were attributed to a serious adverse event occurred during study treatment (ie, primary cause of death other than NSCLC: respiratory insufficiency and hemoptysis [both n = 1; docetaxel alone]; intermittent atrial fibrillation and acute respiratory failure [both n = 1; V100+doc]; and exacerbation of chronic obstructive pulmonary disease and pulmonary embolism [both n = 1; V300+doc]. All were considered by the investigator to be unrelated to study treatments.

	DISCUSSION

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This study assessed vandetanib in combination with docetaxel for patients with platinum-refractory NSCLC. In the run-in phase, the combination was relatively well tolerated with no significant PK interaction. In the randomized phase, PFS was prolonged in both the V100+doc (median PFS, 18.7 weeks; hazard ratio = 0.64) and V300+doc arms (median PFS, 17.0 weeks; hazard ratio = 0.83) compared with docetaxel alone (median PFS, 12.0 weeks). The one-sided P value of .037 for V100+doc versus docetaxel alone is considered statistically significant in relation to the prespecified significance level of .20; (ie, less than 20% probability that the prolongation occurred by chance alone).

These data suggest that the addition of vandetanib to docetaxel increases PFS and objective response rates compared with docetaxel alone. Previous randomized NSCLC studies that combined VEGF or EGFR inhibitors with chemotherapy have yielded mixed results. The addition of bevacizumab to carboplatin and paclitaxel chemotherapy resulted in significantly improved overall survival and increased PFS and objective response rate compared with chemotherapy alone.¹⁶ These results, as well as randomized studies in other solid tumor types,¹⁷ suggest that VEGF blockade using the monoclonal antibody bevacizumab may enhance the effectiveness of chemotherapy. In contrast, adding the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib to standard doublet chemotherapy failed to significantly improve objective response rates or overall survival in four different phase III studies,^18-21 despite the fact that erlotinib monotherapy prolonged overall survival in the second-line setting compared with placebo.²² It has been hypothesized that EGFR blockade may slow proliferation and cause G1 cell cycle arrest in tumor cells with wild-type EGFR,²³ thereby reducing cell cycle phase-dependent activity of chemotherapy. This provides a potential explanation for the failure of EGFR TKIs to enhance the efficacy of doublet chemotherapy in unselected patients with NSCLC, although specific subgroups (eg, nonsmokers) may have benefited.¹⁸

This study was designed to compare the V100+doc and V300+doc arms with the docetaxel-alone control arm, rather than to detect differences between the V100+doc and V300+doc arms. Definitive conclusions are, therefore, not possible, but the data suggest that the antitumor activity may have been higher in patients receiving the lower dose of vandetanib, with a higher response rate and longer time to progression in the V100+doc arm compared with the V300+doc arm. If true, one could speculate that at lower doses of vandetanib, the level of EGFR inhibition is not sufficiently high to antagonize chemotherapy. Furthermore, some preclinical studies of antiangiogenic agents have demonstrated a biphasic dose-response curve,²⁴ illustrating that the maximum-tolerated dose of certain agents may not necessarily be the optimally effective dose. Conversely, a phase II trial comparing low- (7.5 mg/kg) and high- (15 mg/kg) dose bevacizumab with carboplatin and paclitaxel in patients with advanced NSCLC showed a trend towards greater efficacy for the higher dose.²⁵ These data highlight the importance of developing surrogate markers for the assessing target modulation.

The improvements in PFS and objective response rate with the addition of vandetanib did not translate into prolonged overall survival, with the V300+doc arm showing a trend toward shorter survival. One possibility is that the different outcomes for PFS and overall survival may have arisen by chance, given the modest sample size. In this context, patients in the docetaxel-alone arm had a markedly longer overall survival (13.4 months) than indicated in historical data from randomized phase III trials (5.7 to 7.9 months).^26-28 Imbalances in subsequent therapies received and possible sex effects could have contributed to the differences. No increase in poststudy toxic deaths or other treatment-related serious adverse events was observed in the vandetanib arms (data not shown). Notably, randomized phase II testing showed an improvement in PFS, but not overall survival, in NSCLC patients receiving bevacizumab, carboplatin, and paclitaxel compared with carboplatin and paclitaxel alone.²⁵ In the subsequent E4599 trial, an improvement in overall survival was observed in patients with nonsquamous histology receiving this regimen.¹⁶

In an exploratory subset analysis, a trend toward improved PFS was seen in patients with both adenocarcinoma and nonadenocarcinoma histologies treated with vandetanib 100 mg; in the V300+doc arm, a trend towards greater PFS benefit was seen only in the nonadenocarcinoma group (Fig 3). A trend toward greater benefit in females than in males was seen in both vandetanib arms compared with docetaxel alone. Interestingly, a subset analysis of the E4599 trial showed a significant benefit for males, but not females, receiving bevacizumab with chemotherapy compared with chemotherapy alone.¹⁶ The molecular mechanisms underlying possible sex differences merit further investigation.

Randomized phase II trials may be useful for predicting toxicity, assessing dose, and guiding subsequent phase III development. Randomized phase II testing of bevacizumab with carboplatin and paclitaxel showed an increased incidence of life-threatening hemoptysis, which occurred in four of 13 patients with squamous cell histology and two of 54 with adenocarcinoma.²⁵ Fatal hemoptysis has also been reported in two lung cancer patients treated with the VEGFR TKI AG-013736.²⁹ In the current study, four of 37 patients with squamous cell histology experienced hemoptysis: two each in the V100+doc (grade 1 or 2) and docetaxel-alone (grade 3 or 4) arms. No CNS bleeds were observed. The relative absence of major hemoptysis in the vandetanib arms of this study may reflect differences between the patient populations (ie, platinum naïve v platinum refractory), chemotherapy or investigational agent (ie, potency, kinetics, or pharmacology), or chance. Nevertheless, it suggests that patients with squamous cell and other histologic subtypes may be treated safely with vandetanib.

In summary, the combination of docetaxel and vandetanib was generally well tolerated, even in patients with squamous cell histology, with no significant PK interaction between the two agents. The study achieved its primary objective of PFS prolongation in patients receiving vandetanib 100 mg plus docetaxel (hazard ratio = 0.64, one-sided P = .037 in relation to the prespecified one-sided significance level of .20), with improvements in objective response rate and disease control rate also observed. A randomized phase III trial of docetaxel with or without vandetanib (100 mg) has been initiated.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their 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.

Employment: Sarah J. Kennedy, AstraZeneca; Jeannie Hou, AstraZeneca Leadership: N/A Consultant: John V. Heymach, AstraZeneca; Bruce E. Johnson, Genzyme; Roy S. Herbst, AstraZeneca Stock: N/A Honoraria: Roy S. Herbst, AstraZeneca Research Funds: John V. Heymach, Funds, AstraZeneca; Milo Peek, Funds, AstraZeneca; Shirish Gadgeel, Funds, AstraZeneca; Roy S. Herbst, Funds, AstraZeneca Testimony: N/A Other: Bruce E. Johnson, Royalties, patent on EGFR testing

	AUTHOR CONTRIBUTIONS

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Conception and design: John V. Heymach, Bruce E. Johnson, Chandra P. Belani, Roy S. Herbst

Financial support: Jeannie Hou

Administrative support: Jeannie Hou

Provision of study materials or patients: John V. Heymach, Bruce E. Johnson, Diane Prager, Jaromir Roubec, Milo Peek, Chandra P. Belani, Istvan Bodrogi, Shirish Gadgeel, Jeannie Hou, Roy S. Herbst

Collection and assembly of data: Bruce E. Johnson, Edit Csada, Milo Peek, Irena pásová, Chandra P. Belani, Sarah J. Kennedy, Jeannie Hou, Roy S. Herbst

Data analysis and interpretation: John V. Heymach, Bruce E. Johnson, Chandra P. Belani, Sarah J. Kennedy, Jeannie Hou, Roy S. Herbst

Manuscript writing: John V. Heymach, Bruce E. Johnson, Chandra P. Belani, Sarah J. Kennedy, Jeannie Hou, Roy S. Herbst

Final approval of manuscript: John V. Heymach, Bruce E. Johnson, Edit Csada, Chandra P. Belani, Jeannie Hou, Roy S. Herbst

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Vandetanib plasma concentrations ± docetaxel. Samples: ‘– docetaxel’ collected on day 21 (ie, 20 days after administration of docetaxel on day 1); ‘+ docetaxel’ collected on day 22 for up to 24 h after administration of docetaxel. Data are shown as the geometric mean ± SD of samples from up to 4 (vandetanib 100 mg + docetaxel) or 8 (vandetanib 300 mg + docetaxel) assessable patients. Plasma concentrations were determined using a validated high performance liquid chromatography method with tandem mass spectrometric detection.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A2. Docetaxel plasma concentrations ± vandetanib. Samples: ‘– vandetanib’ collected on day 1; ‘+ vandetanib’ collected on day 22 (ie, after steady-state exposure to vandetanib had been achieved). Data are shown as the geometric mean ± SD of samples from up to 4 (vandetanib 100 mg + docetaxel) or 8 (vandetanib 300 mg + docetaxel) assessable patients. Plasma concentrations were determined using a validated high performance liquid chromatography method with tandem mass spectrometric detection.

View this table: [in this window] [in a new window]   Table A1. Adverse Events, Irrespective of Causality, Reported in 25% of Patients Overall (run-in phase)

	ACKNOWLEDGMENTS

 
The following individuals were also investigators in this study: Pal Magyar, Milan Kuta, Gabor Kovacs, Roger Cohen, Janos Strausz, William Purcell, Troy Guthrie, Maria Szilasi, John Cole, Jana Skrickova, Jeffrey Crawford, Philip Stella, Robert Bolin, Hal Gerstein, Harvey Zimbler, Charles Henderson, Frantisek Salajka, and William Cook. We thank John Matthew for editorial assistance.

	NOTES

 
Supported by AstraZeneca. J.V.H. is a Damon Runyon-Lilly Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI 24-04) and the American Society for Clinical Oncology Career Development Award.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA; 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain; and the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

ZACTIMA is a trademark of the AstraZeneca group of companies.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 20, 2006; accepted June 28, 2007.

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