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Keywords:

  • antineoplastic combined chemotherapy protocol;
  • Asian continental ancestry group;
  • bevacizumab;
  • non-small cell lung cancer;
  • vascular endothelial growth factor

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Aim:  The phase III AVAiL study evaluated the efficacy and safety of the anti-vascular epidermal growth factor agent bevacizumab combined with platinum-based chemotherapy as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC). We report the results of a preplanned analysis of Asian patients enrolled in AVAiL.

Methods:  Patients with recurrent or advanced non-squamous NSCLC were randomized to receive bevacizumab 7.5 mg/kg, bevacizumab 15 mg/kg or placebo, plus cisplatin 80 mg/m2 and gemcitabine 1250 mg/m2 for up to six cycles, followed by bevacizumab or placebo until disease progression. An exploratory analysis was undertaken to assess efficacy and safety in an Asian subgroup.

Results:  Of the 1043 patients enrolled, 105 were Asian and were included in the subgroup analysis. Progression-free survival was 8.5 months (95% CI 7.3–10.8) in the bevacizumab 15-mg/kg group, 8.2 (95% CI 6.6–11.7) in the 7.5-mg/kg group and 6.1 (95% CI 5.1–8.0) in the placebo group. Median overall survival in the 7.5-mg/kg bevacizumab group was prolonged compared with placebo group (HR 0.46; 95% CI 0.22–0.97). Nausea was the most common adverse event, occurring at similar rates (ranging from 69–76%) in all study groups. Hypertension was the most common adverse event of special interest, seen in 29, 55 and 16% of patients in the 7.5-mg/kg and 15-mg/kg bevacizumab and placebo groups, respectively.

Conclusion:  Study results strongly suggest that bevacizumab at a dose of 7.5 mg/kg improves the duration of overall survival when combined with cisplatin-gemcitabine in Asian patients. Bevacizumab was well tolerated in this patient group.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Lung cancer is the most common cause of cancer mortality, responsible for close to 1 million deaths per year worldwide1 and non–small-cell lung cancer (NSCLC) represents approximately 85% of all lung cancers.2 Despite advances in treatment, the burden of lung cancer in East Asia remains high, with an incidence of over 435 000 cases yearly.1 A study from Japan demonstrates an increase in lung cancer incidence in women from 1989 to 2002 (annual change of 1.77%; P < 0.05).3 Further, a Japanese cohort study that found cancer to be the leading cause of death in a general population of adults aged 30–79 years (at the time of study entry) reported lung cancer to be the third most common cause of cancer death in both sexes, accounting for 15.0 and 11.4% of the total years of life lost in men and women, respectively. Lung cancer shortened each patient's life by 11.7 years for men and 16.1 years for women.4 Data from the Singapore Cancer Registry for the years 1998–2002 indicate 10-year relative survival ratios of only 5.2% for men and 7.2% for women with lung cancer at any stage; the prognoses for those with advanced disease are even poorer.5 While surgery can be performed on patients with early-stage NSCLC, patients commonly develop local or distant recurrence or second lung primaries. Additionally, more often than not the disease is already advanced at the time of initial diagnosis.6 Thus, systemic therapy is important for prolonging survival in both early and advanced disease.7

Management of advanced NSCLC involves controlling or preventing symptoms with minimal toxicity to the patient.8 Platinum-based doublet chemotherapy has traditionally been standard first-line treatment for advanced NSCLC in Asia.7 However, current chemotherapy regimens, while moderately improving overall survival (OS), have reached a plateau in their effectiveness9 and also cause serious adverse effects (AE) such as vomiting, renal toxicity and cytopenia.10 Significant developments have occurred over the past decade in NSCLC treatment; specifically, newer therapies directed at the molecular signaling mechanisms that promote NSCLC progression are now available and offer added clinical benefit.11,12

Vascular endothelial growth factor (VEGF) helps control angiogenesis in both normal and malignant tissue.13 Bevacizumab is a humanized, murine monoclonal antibody with high specificity and affinity for VEGF-A that blocks binding of the growth factor to its receptor.14 The medication is effective against a variety of malignancies, including metastatic colon cancer15 and was the first targeted agent to improve outcomes when added to standard chemotherapy in advanced NSCLC.

Bevacizumab has demonstrated efficacy as a first-line treatment for non-squamous NSCLC in two randomized phase III studies. In the Eastern Cooperative Oncology Group 4599 trial, bevacizumab every 3 weeks plus carboplatin-paclitaxel improved OS and progression-free survival (PFS) compared with carboplatin-paclitaxel alone in 878 patients with recurrent or advanced non-squamous NSCLC and with no brain metastases.16 The hazard ratio (HR) for OS was 0.79 (P = 0.003) and for PFS it was 0.66 (P < 0.001) in favor of treatment with bevacizumab. Median survival time improved from 10.3 to 12.3 months with the addition of bevacizumab to carboplatin-paclitaxel, and the response rate increased from 15 to 35%.16 In a sub-analysis of patients by histological subtype, adenocarcinoma histology (68.6% of patients) had a median OS of 10.3 months for paclitaxel-carboplatin alone and 14.2 months for paclitaxel-carboplatin and bevacizumab.17

The Avastin in Lung (AVAiL, BO17704) trial was a randomized, placebo-controlled phase III study that assessed the efficacy and safety of bevacizumab 7.5 mg/kg and 15 mg/kg every 3 weeks plus cisplatin-gemcitabine (CG) for treatment of advanced non-squamous NSCLC.18 Demographic and baseline characteristics of the intent-to-treat (ITT) patient population were well balanced across treatment groups. PFS, the primary end-point of the study, was prolonged with bevacizumab-based treatment compared with placebo.18 The HR was 0.75 for the 7.5-mg/kg bevacizumab group (95% confidence interval [CI] 0.62–0.91, P = 0.003) and 0.82 and 15-mg/kg group (95% CI 0.68–0.98, P = 0.03). Median PFS was 6.7 months for the 7.5-mg/kg bevacizumab group and 6.5 months for the 15-mg/kg group (vs 6.1 months for placebo). Objective response rates were 37.8% for the 7.5-mg/kg group and 34.6% for the 15-mg/kg group (vs 21.6% for placebo; P ≤ 0.0001 and P = 0.0002, respectively). However, the PFS benefit seen with bevacizumab-based therapy did not translate into a statistically significant OS benefit at the final analysis, perhaps because of wide utilization of effective second-line treatments. Bevacizumab was well tolerated in this study, with no new safety signals.

Additionally, the single arm non-comparative phase IV Safety of Avastin in Lung Cancer – SAiL (MO19390) study evaluated the safety of first-line bevacizumab together with first-line chemotherapy regimens in recurrent or advanced non-squamous NSCLC.19 The incidence of grade ≥ 3 AE of special interest (AESI) was small (16%), with 77% of these resolving or improving during the study. Overall, the drug regimen was well tolerated with a low rate (9%) of dose interruption or permanent discontinuation due to AESI.

A small (n = 180), randomized phase II study of chemotherapy-naive Japanese patients with advanced non-squamous NSCLC (JO19907) showed an increase in both PFS and response rate when bevacizumab was added to carboplatin-paclitaxel, with a HR of 0.61 (P = 0.0090). The median duration of response was 6.9 months and 5.9 months for bevacizumab + carboplatin-paclitaxel and carboplatin-paclitaxel alone, respectively.20 Yet there have been only a small number of clinical trials of bevacizumab in most Asian countries. Therefore, an exploratory subgroup analysis of AVAiL was conducted to study the efficacy (PFS, OS) and safety of bevacizumab plus CG in Asian patients and to examine these results within the overall framework of bevacizumab therapy for patients with advanced non-squamous NSCLC.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Patient population

A total of 1043 patients were enrolled in the study, with 150 centers opened for recruitment in 20 countries across Europe, Eastern Asia, Australia, Central and South America, and Canada between February 2005 and August 2006. An exploratory subgroup analysis was undertaken to assess the treatment's efficacy and safety in the Asian subpopulation (defined as patients of East Asian ethnicity), which comprised patients recruited from Taiwan (five centers), Hong Kong (three centers), and Thailand (three centers). The protocol was approved by local independent ethics committees.

Full details of the AVAiL trial inclusion and exclusion criteria have been published previously.18,21 Patients older than 18 years who had histologically or cytologically documented advanced (stage IIIb, with supraclavicular lymph node metastasis or malignant pleural or pericardial effusion, or stage IV) or recurrent non-squamous NSCLC and were chemotherapy-naive were eligible to participate in this trial. Mixed non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component were not allowed. Epidermal growth factor receptor (EGFR) mutation status was not collected or tested for the purposes of this analysis.

Study design

This was a multicenter, randomized, double-blind study in which patients with advanced or recurrent non-squamous NSCLC who had not had prior chemotherapy received CG with bevacizumab (7.5 or 15 mg/kg) or CG with high-dose or low-dose placebo. Patients were allocated to treatment assignment by a centralized stratified random assignment procedure. Because only one size of bevacizumab vial was available, the placebo arm was split into high-dose and low-dose groups to preserve the blind to trial treatment. High-dose and low-dose placebo patients were pooled for all analyses.

Cisplatin was administered i.v. at 80 mg/m2 on day 1 and gemcitabine was administered i.v. at 1250 mg/m2 on days 1 and 8. Chemotherapy was repeated every 3 weeks for up to six cycles unless there was evidence of disease progression or unacceptable toxicity. Placebo or bevacizumab was administered i.v. and given concurrently with chemotherapy every 3 weeks on day 1. Placebo patients were not allowed to cross over to bevacizumab. Additional details regarding drug administration, stratification and other strategies to maintain blinding have been published previously.18

After the clinical cut-off for PFS analysis (7 October 2006), patients receiving trial medication were allowed to remain on the dose of bevacizumab to which they had been randomized and were followed up according to the study schedule of assessments. The final clinical cut-off date was extended to 30 November 2007.

During the trial, tumor response was assessed by the investigator every three cycles (approximately every 9 weeks) according to response evaluation criteria in solid tumors (RECIST) version 1.0.22 Adverse events were graded and recorded according to the National Cancer Institute common toxicity criteria for adverse events version 3.0.

Statistical analysis

Efficacy analyses were based on a subgroup of the ITT group, which included all randomized patients. Prior to breaking the treatment allocation blind for the initial interim analysis, the primary efficacy parameter of the study was changed from OS to PFS, in order to prevent the OS end-point being confounded by the growing use of second-line therapies and to set a more reliable primary end-point for efficacy assessment. PFS was defined as the time from random assignment to first documented disease progression by RECIST or due to clinical deterioration or death, whichever occurred first. Comparisons of PFS between treatment arms were made using a 2-sided log–rank test with an overall α level of 0.05 and 80% power.

Other planned analyses included OS, response rate, duration of response, and safety. The safety population included all patients who were randomly assigned and had received at least one dose of trial treatment. The trial was not powered to allow a direct comparison of the two bevacizumab-containing arms.

A preplanned exploratory subanalysis assessed the effects of bevacizumab in Asian patients. HR, along with 95% exact CI, were computed based on a Cox regression analysis. Event-time distributions were estimated using the Kaplan–Meier method to determine the median survival estimates for PFS and OS. All analyses reported here were carried out from a data cut-off on 30 November 2007.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Patients

Overall, 1043 patients were enrolled and randomized. Of these, 105 were Asian: 33 were randomized to CG + placebo, 38 to CG + bevacizumab 7.5 mg/kg and 34 to CG + bevacizumab 15 mg/kg. Table 1 documents the characteristics of the Asian patient subgroup. More than half of the patients were non-smokers and most had stage IV disease at baseline.

Table 1.  Patients' characteristics by treatment group
ParameterPlacebo + CG (n = 33)Bevacizumab 7.5-mg/kg + CG (n = 38)Bevacizumab 15 mg/kg + CG (n = 34)
  1. CG, cisplatin-gemcitabine; ECOG, Eastern Cooperative Oncology Group, SD, standard deviation.

Age (years)   
 Mean (SD)56.8(11.5)57.1(10.1)57.2(11.6)
 Median(range)57.0(29–75)56.5(26–73)56.5(35–79)
Sex, n(%)   
 Male18(55)19(50)18(53)
 Female15(45)19(50)16(47)
ECOG performance status, n(%)   
 015(45)18(47)18(53)
 118(55)20(53)16(47)
Smoking status, n(%)   
 Never19(58)25(66)19(56)
 Past11(33)10(26)13(38)
 Current3(9)3(8)2(6)
Disease stage, n(%)   
 IIIb without effusion3(9)3(8)3(9)
 IIIb with effusion2(6)2(5)2(6)
 IV25(76)31(82)28(82)
 Recurrent3(9)2(5)1(3)
Diagnosis by, n(%)   
 Histology20(61)26(68)20(59)
 Cytology13(39)12(32)14(41)
Cellular classification, n(%)   
 Adenocarcinoma29(88)36(95)29(85)
 Large cell carcinoma1(3)1(3)2(6)
 Mixed with predominantly adenocarcinoma component1(3)0(0)1(3)
 Other2(6)1(3)2(6)

Efficacy

An increase in PFS was observed in both doses of bevacizumab + CG compared with CG + placebo in the Asian patient subanalysis. The HR was 0.65 for the 15-mg/kg (95% CI 0.35–1.22) and 0.6 in the 7.5-mg/kg group (95% CI 0.32–1.13). The reported median PFS was 8.5 months (95% CI 7.3–10.8) in the bevacizumab 15-mg/kg arm, 8.2 months (95% CI 6.6–11.7) in the 7.5-mg/kg arm and 6.1 months (95% CI 5.1–8.0) in the placebo arm (Fig. 1). Asian patients in the CG + bevacizumab 7.5-mg/kg group achieved improvements in OS compared with those in the CG + placebo group (HR 0.46; 95% CI 0.22–0.97). Patients in the CG + bevacizumab 15-mg/kg arm did not show a significant increase in OS, however (HR 0.79; 95% CI 0.40–1.57).

image

Figure 1. Plot of Kaplan–Meier estimates for progression-free survival in the Asian subgroup showing (inline image) placebo, (inline image) bevacizumab (Bev) 15 mg/kg + cisplatin/gemcitabine and (inline image) Bev 7.5 mg/kg + cisplatin-gemcitabine.

Download figure to PowerPoint

The number of Asian patients with measurable disease at baseline who had an objective response (complete or partial) was higher in the bevacizumab-containing arms (48.5% in the 7.5-mg/kg arm and 27.6% in the 15-mg/kg arm) compared with the placebo-containing arm (10.3%). Of note, no patients in either of the bevacizumab groups had progressive disease; whereas five patients (17.2%) in the placebo-containing arm were found to have progressive disease.

Safety

A total of 98 Asian patients (93%) experienced at least one AE ≥ grade 1, which were classified by investigators as either unrelated to the trial treatment or as remotely, possibly or probably related to the trial treatment (including both chemotherapy and bevacizumab). In all 29 patients (28%) receiving 7.5-mg/kg and 27 patients (26%) receiving 15 mg/kg bevacizumab + CG experienced an AE that was probably related to treatment, compared with 20 (19%) patients receiving placebo + CG. The most common clinical AE observed was nausea, reported in 24 (69%) patients in the bevacizumab 7.5-mg/kg group, 25 (76%) in the 15-mg/kg group and 23 (74%) in the placebo group. This is similar to the main patient population. Adverse events led to the discontinuation of treatment in 23, 30 and 13% of the 7.5-mg/kg and 15-mg/kg bevacizumab + CG and placebo + CG arms, respectively, in the Asian subgroup.

A total of 81 patients had an AE grade 3 or higher, with 66 patients having AE that were deemed related to the trial treatment. The 7.5-mg/kg bevacizumab + CG group and the 15-mg/kg bevacizumab + CG group both had 27 ≥ grade 3 events each (77% and 82%, respectively). The rate of AE was slightly lower in the placebo group, with a total of 22 patients (71%).

A total of 55 Asian patients (52%) in the safety group had ≥1 AESI (e.g. hypertension, bleeding, proteinuria, thrombotic events and wound-healing complications) (Table 2). While most of these AEs were grades 1 or 2, 13 of them, occurring in 12 patients, were ≥ grade 3. The most common AESI was hypertension, exhibited by 10 (29%), 18 (55%) and five (16%) patients in the 7.5-mg/kg and 15-mg/kg bevacizumab + CG and placebo + CG groups, respectively. A total of eight patients discontinued drug therapy because of an AESI (four patients in the bevacizumab 7.5-mg/kg group, three in the 15-mg/kg group and one in the placebo group).

Table 2.  Adverse events of special interest according to National Cancer Institute Common toxicity criteria for adverse events version 3.0 grade
Adverse eventNumber of patients (%)
Placebo (n = 31)Bevacizumab 7 mg/kg + CG (n = 35)Bevacizumab 15 mg/kg + CG (n = 33)
Grade 1/2Grade ≥ 3Grade 1/2Grade ≥ 3Grade 1/2Grade ≥ 3
  • Includes cerebral, gastric, gastrointestinal, lower gastrointestinal, and rectal. CG, cisplatin/gemcitabine.

Hypertension5(16.1)0(0)7(20.0)3(8.6)16(48.5)3(9.1)
Bleeding4(12.9)0(0)15(42.9)1(2.9)17(51.5)1(3.0)
Proteinuria0(0)0(0)3(8.6)0(0)2(6.1)2(6.1)
Thromboembolic events      
 Venous2(6.5)1(3.2)1(2.9)1(2.9)1(3.0)1(3.0)
 Arterial0(0)0(0)1(2.9)0(0)0(0)0(0)
Wound healing complications0(0)0(0)1(2.9)0(0)1(3.0)0(0)
Hemorrhage0(0)0(0)2(5.7)1(3.0)3(9.1)0(0)

Serious adverse events (SAE) related to trial treatment occurred in a total of 21 patients (20%), of which eight (23%) and nine patients (27%), suffered SAE in the 7.5-mg/kg and 15-mg/kg bevacizumab + CG groups, respectively. Fewer patients had SAE in the placebo group (four patients; 13%) (Table 2).

Overall, 715 randomized patients had died by the final clinical cut-off date. In the Asian patient subgroup, nine (27%) in the placebo + CG group, two (5%) in the bevacizumab 7.5-mg/kg + CG group and six (18%) in the 15-mg/kg + CG group were dead at the clinical cut-off date (Table 2).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

Platinum-based chemotherapy agents have a proven role in controlling symptoms and prolonging survival in NSCLC. However, the addition of molecular-targeted therapies to these regimens represents a significant step forward in first-line treatment of this disease, as these medications can improve the efficacy outcomes seen with chemotherapy alone. This subgroup analysis examined the efficacy and safety of the anti-VEGF monoclonal antibody bevacizumab in Asian patients enrolled in the AVAiL trial, and found that bevacizumab + CG was effective at extending PFS in Asian patients with advanced NSCLC, although, contrary to the findings of the main trial, the survival benefit did not reach statistical significance. Additionally, a statistically significant OS benefit was not observed in the overall AVAiL patient group, but OS was prolonged in Asian patients receiving bevacizumab 7.5-mg/kg. The protocol-defined primary end-point of prolonged PFS with bevacizumab-based therapy was met in the ITT population and PFS was also observed to be prolonged when analyzed in an exploratory manner at the final data cut-off date of AVAiL. Response rate and response duration were also improved in the ITT population. These previously reported results demonstrate a clinically meaningful reduction in the risk of progressing at any time for patients in the bevacizumab treatment groups,18,21 a finding corroborated by similar studies of bevacizumab therapy in NSCLC (C-M Tsai, JSK Au, GC Chang et al., unpublished data).16

The findings of this Asian subgroup analysis are similar to those of the SAiL trail Asian subgroup analysis. While the SAiL trial was of a phase IV design and did not have a control arm, the results showed an increased time in median OS (7.5-mg/kg dose: 28 months [HR 0.46] and 15-mg/kg dose: 26 months [HR 0.79], vs 17.4 months in the ITT population). Also of note, the rate for complete response plus partial response in the bevacizumab arm was 10.3%, considerably lower than found in the literature. However, the rates for stable disease were 65.5% in the placebo + CG arm versus 36.4% in the 7.5-mg/kg bevacizumab + CG arm and 65.5% in 15-mg/kg bevacizumab + CG arm.

Subgroup analyses themselves have inherent limitations; a treatment effect is more likely to be lacking in subgroups due to the potential heterogeneity of the treatment effect between each group, particularly when the number of patients is small.23 However, in instances where heterogeneity of treatment effect is expected due to pathophysiological or biological variation, or both, within the study population (as noted in this study), subgroup analyses can be useful.23 Asian ethnicity alone can be a positive predictor of increased OS in NSCLC, even after controlling for smoking status.24,25 Further, clinical benefits of treatment with tyrosine kinase inhibitors (TKI) of the EGFR have been reported to be greater for Asian patients, which is likely to be because somatic EGFR mutations are found more frequently in patients of Asian ethnicity.10,26,27 This could potentially influence the subgroup analysis results when they are compared to those of the ITT analysis. Furthermore, observed differences in characteristics between the 7.5-mg/kg and 15-mg/kg bevacizumab + CG groups may have contributed to discrepant OS outcomes. There was a larger proportion of adenocarcinoma patients in the 7.5-mg/kg study arm, which may have led to an overrepresentation of patients with EGFR-positive mutations. These patients may have received a greater number of TKI therapies in subsequent lines of treatment and therefore this may have led to a relative increase in OS for this treatment arm. However, EGFR mutations were not tested in the analysis and therefore this cannot be known conclusively. Additionally, the 7.5-mg/kg group had a higher proportion of patients who never smoked (66 vs 56%), which could have also led to an OS improvement for the 7.5-mg/kg treatment arm.

The issue of subsequent treatment is also one of the limitations of the overall AVAiL study. Although a number of effective second-line therapies for NSCLC came into widespread use during the time of AVAiL, no post-progression treatment was specified in the protocol, which may have led to a potential bias in the OS analysis. This sort of bias introduced by second-line therapies has been noted in other studies.28,29 In fact, more than 60 distinct regimens were subsequently used by 62% (spread evenly across treatment groups) of the total patient population. Generally speaking, it is difficult to specify post-progression therapy within a protocol as these treatments need to be tailored to each individual patient. While OS is considered the gold standard for oncology trial outcomes, variations in subsequent therapies can confound results. In study designs where subsequent therapies cannot be controlled for, PFS may be a reasonable proxy for OS.30

It is important to note that this subgroup analysis was not adjusted to account for multiplicity. This is a general limitation of the analysis; however, specifically, the lack of adjustment for multiplicity translates to an increased likelihood of type 1 error. This could potentially impact on the study findings, including the statistically significant difference in OS benefit for Asian patients taking 7.5-mg/kg bevacizumab. Despite this limitation, the study findings are consistent with those of an Asian patient subanalysis of the SAiL trial, a phase IV study also involving bevacizumab. Although this study had no control arm, the study found a median OS of 18.9 months (95% CI: 17.4–20.7), based on 152 patients.

Safety results at the time of follow-up analysis did not reveal any new safety signals. The outcomes were consistent with those previously reported.18,19 Results from the subgroup analysis in Asian patients of the SAiL phase IV trial additionally confirm the low incidence of clinically significant AE (grade ≥ 3) in the Asian subgroup.

In conclusion, at the time of the protocol-defined final analysis, the addition of bevacizumab to CG chemotherapy numerically improved PFS in Asian patients. Study data strongly suggest that bevacizumab 7.5-mg/kg + CG also prolonged OS, although the results of this subgroup analysis should be interpreted with caution. Subsequent studies will be necessary to confirm these results.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES

This study was supported by F. Hoffman-La Roche AG. Analytica International Inc. and Elizabeth Smith (through funding from F. Hoffmann-La Roche AG) provided writing assistance to the authors in the preparation of this manuscript.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGEMENTS
  8. REFERENCES
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